6-Substituted pyrido-pyrimidines

ABSTRACT

The present invention provides compounds of the Formula I and II:  
                 
 
     wherein R 1 , R 3 , W, Z, X 1 , X 2 , Ar 1 , R 8  and R 9  are as defined herein, and methods and intermediates for their preparation and uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under Title 35 U.S.C. §119 (e),of U.S. Provisional Application Serial No. 60/268,375, filed Feb. 12,2001, and Serial No. 60/334,5654, filed Nov. 30, 2001, the disclosuresof which are herein incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to pyridopyrimidines andderivatives thereof. In particular, the present invention provides2,6-disubstituted 7-oxo-pyrido[2,3-d]pyrimidines, a process for theirmanufacture, pharmaceutical preparations comprising the same, andmethods for using the same.

BACKGROUND OF THE INVENTION

[0003] Mitogen-activated protein kinases (MAP) is a family ofproline-directed serine/threonine kinases that activate their substratesby dual phosphorylation. The kinases are activated by a variety ofsignals including nutritional and osmotic stress, UV light, growthfactors, endotoxin and inflammatory cytokines. One group of MAP kinasesis the p38 kinase group that includes various isoforms (e.g., p38α,p39β, p38γ and p38δ). The p38 kinases are responsible forphosphorylating and activating transcription factors as well as otherkinases, and are activated by physical and chemical stress,pro-inflammatory cytokines and bacterial lipopolysaccharide.

[0004] More importantly, the products of the p38 phosphorylation havebeen shown to mediate the production of inflammatory cytokines,including TNF and IL-1, and cyclooxygenase-2. Each of these cytokineshas been implicated in numerous disease states and conditions. Forexample, TNF-α is a cytokine produced primarily by activated monocytesand macrophages. Its excessive or unregulated production has beenimplicated as playing a causative role in the pathogenesis of rheumatoidarthritis. More recently, inhibition of TNF production has been shown tohave broad application in the treatment of inflammation, inflammatorybowel disease, multiple sclerosis and asthma.

[0005] TNF has also been implicated in viral infections, such as HIV,influenza virus, and herpes virus including herpes simplex virustype-1(HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus(CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8(HHV-8), pseudorabies and rhinotracheitis, among others.

[0006] Similarly, IL-1 is produced by activated monocytes andmacrophages, and plays a role in many pathophysiological responsesincluding rheumatoid arthritis, fever and reduction of bone resorption.

[0007] Additionally, the involvement of p38 has been implicated instroke, Alzheimer's disease, osteoarthritis, lung injury, septic shock,angiogenesis, dermatitis, psoriasis and atopic dermatitis. J. Exp. Opin.Ther. Patents, (2000) 10(1).

[0008] The inhibition of these cytokines by inhibition of the p38 kinaseis of benefit in controlling, reducing and alleviating many of thesedisease states.

[0009] Certain 6-aryl-pyrido[2,3-d]pyrimidin-7-ones, -7-imines and-7-thiones are disclosed as inhibitors of protein tyrosine kinasemediated cellular proliferation in WO 96/34867, published Nov. 7, 1996(Warner Lambert). Other 6-aryl-pyrido[2,3-d]pyrimidines andnaphthyridines are also disclosed as inhibitors of tyrosine kinase in WO96/15128, published May 23, 1996 (Warner Lambert).6-alkyl-pyrido[2,3-d]pyrimidin-7-ones are disclosed as inhibitors ofcyclin-dependent kinases in WO 98/33798, published Aug. 6, 1998 (WarnerLambert). Certain 4-amino-pyridopyrimidines are disclosed as inhibitorsof dihydrofolate reductase in EP 0 278 686A1, published Aug. 8, 1988(Wellcome Foundation).

SUMMARY OF THE INVENTION

[0010] One aspect of the present invention provides compoundsrepresented by Formula I and II:

[0011] or pharmnaceutically acceptable salts thereof,

[0012] wherein:

[0013] Z is N or CH;

[0014] W is NR^(2;)

[0015] X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S, or CR⁵R⁶ (whereR⁵ and R⁶ are independently hydrogen or alkyl) or C═O;

[0016] X² is O or NR;

[0017] Ar¹ is aryl or heteroaryl;

[0018] R² is hydrogen alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl,heteroalkylcarbonyl, heteroalkyloxycarbonyl or —R²¹—R²² where R²¹ isalkylene or —C(═O)— and R is alkyl or alkoxy;

[0019] R¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstitutedcycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl,heterocyclyl, heterocyclylalkyl, R¹²—SO₂-heterocycloamino (where R¹² ishaloalkyl, aryl, aryalkyl, heteroaryl or heteroaralkyl), —Y¹—C(O)—Y²—R¹¹(where Y¹ and Y² are independently either absent or an alkylene groupand R¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino,monoalkylamino or dialkylamino), (heterocyclyl)(cycloalkyl)alkyl or(heterocyclyl)(heteroaryl)alkyl;

[0020] R³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R³¹ (whereR³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino ordialkylamino), amino, monoalkylamino, dialkylamino or NR³²—Y³—R³³ (whereY³ is —C(O), —C(O)O—, —C(O)NR³⁴, S(O)₂ or S(O)₂NR³¹; R³², R³⁴ and R³⁵are independently hydrogen or alkyl; and R³³ is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substitutedphenyl)or acyl;

[0021] R⁷ is hydrogen or alkyl; and

[0022] R⁸ and R⁹ are independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl,—C(O)—R⁸¹ (where R⁸is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, alkoxy, aryloxy, amino, mono- or di-alkylamino, arylaminoor aryl(alkyl)amino) or R⁸ and R⁹ together form ═CR⁸²R⁸³ (where R¹¹ andR⁸³ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl oroptionally substituted phenyl).

[0023] Another aspect of the present invention provides a pharmaceuticalformulation comprising a Compound of Formula I or II and apharmaceutically acceptable carrier, diluent, or excipient therefor.

[0024] Compounds of Formula I and II and their aforementioned salts areinhibitors of protein kinases, and exhibit effective activity againstp38 in vivo. They are also surprisingly selective against p38 kinaserelative to cyclin-dependent kinases and tyrosine kinases. Therefore,compounds of the present invention can be used for the treatment ofdiseases mediated by the pro-inflammatory cytokines such as TNF andIL-1. Thus, another aspect of the present invention provides a methodfor treating p38 mediated diseases or conditions in which atherapeutically effective amount of a Compound of Formula I or II isadministered to a patient in need of such treatment.

[0025] Yet another aspect of the present invention provides a method forpreparing the compounds described above and intermediates intermediatesof Formula I′ and II″useful therefor.

[0026] wherein:

[0027] Z is N or CH;

[0028] W is S, S(O), S(O)₂ or O;

[0029] X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S, or CR⁵R⁶ (whereR⁵ and R⁶ are independently hydrogen or alkyl) or C═O;

[0030] X² is O or NR⁷;

[0031] Ar¹ is aryl or heteroaryl;

[0032] R¹⁰ is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl, orR¹⁰W together form a leaving group or hydroxy;

[0033] R³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R³¹ (whereR³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino ordialkylamino), amino, monoalkylamino, dialkylamino or NR³²—Y³—R³³ (whereY³ is —C(O), —C(O)O—, —C(O)NR³⁴, S(O)₂, or S(O)₂NR³¹; R³², R³⁴ and R³⁵are independently hydrogen or alkyl; and R³³ is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substitutedphenyl) or acyl;

[0034] R⁷ is hydrogen or alkyl; and

[0035] R⁸ and R⁹ are independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl,—C(O)—R⁸¹ (where R⁸¹is alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- anddi-alkylamino, arylamino or aryl(alkyl)amino) or R⁸ and R⁹ together form═CR⁸²R⁸³ (where R⁸² and R⁸³ are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl or optionally substituted phenyl).

DEFINITIONS

[0036] Unless otherwise stated, the following terms used in thespecification and claims have the meanings given below:

[0037] “Acyl” means a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl,cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein.Representative examples include, but are not limited to formyl, acetyl,cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl,and the like.

[0038] “Acylamino” means a radical —NR′C(O)R, where R′ is hydrogen oralkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkylare as defined herein. Representative examples include, but are notlimited to formylamino, acetylamino, cylcohexylcarbonylamino,cyclohexylmethylcarbonylamino, benzoylamino, benzylcarbonylamino, andthe like.

[0039] “Alkoxy” means a radical —OR where R is an alkyl as definedherein e.g., methoxy, ethoxy, propoxy, butoxy and the like.

[0040] “Alkyl” means a linear saturated monovalent hydrocarbon radicalof one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl,propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.

[0041] “Alkylene” means a linear saturated divalent hydrocarbon radicalof one to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

[0042] “Alkylthio” means a radical —SR where R is an alkyl as definedabove e.g., methylthio, ethylthio, propylthio, butylthio, and the like.

[0043] “Aryl” means a monovalent monocyclic or bicyclic aromatichydrocarbon radical which is optionally substituted independently withone or more substituents, preferably one, two or three, substituentspreferably selected from the group consisting of alkyl, hydroxy, alkoxy,haloalkyl, haloalkoxy, Y—C(O)—R (where Y is absent or an alkylene groupand R is hydrogen, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, amino,monoalkylamino or dialkylamino), heteroalkyl, heteroalkyloxy,heteroalkylamino, halo, nitro, cyano, amino, monoalkylamino,dialkylamino, alkylsulfonylamino, heteroalkylsulfonylamino, sulfonamido,methylenedioxy, ethylenedioxy, heterocyclyl or heterocyclylalkyl. Morespecifically the term aryl includes, but is not limited to, phenyl,chlorophenyl, methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl,1-naphthyl, 2-naphthyl, and the derivatives thereof.

[0044] “Aryloxy” means a radical —OR where R is an aryl as definedherein e.g. phenoxy.

[0045] “Aryloxycarbonyl” means a radical R—C(═O)— where R is aryloxy,e.g. phenoxycarbonyl.

[0046] “Cycloalkyl” refers to a saturated monovalent cyclic hydrocarbonradical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl,cyclohexyl, 4-methyl-cyclohexyl, and the like.

[0047] “Cycloalkylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is cycloalkyl group as defined herein, e.g.,cyclohexylmethyl, and the like.

[0048] “Substituted cycloalkyl” means a cycloalkyl radical as definedherein with one, two or three (preferably one) ring hydrogen atomsindependently replaced by cyano or —Y—C(O)R (where Y is absent or analkylene group and R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy,amino, monoalkylamino, dialkylamino, or optionally substituted phenyl).

[0049] “Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, hydroxyalkyl, cycloalkyl, or cycloalkylalkyl groupas defined herein. Representative examples include, but are not limitedto dimethylamino, methylethylamino, di(1-methylethyl)amino,(methyl)(hydroxymethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino,(cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino, and thelike.

[0050] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoroand chloro.

[0051] “Haloalkyl” means alkyl substituted with one or more same ordifferent halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and thelike.

[0052] “Heteroalkyl” means an alkyl radical as defined herein whereinone, two or three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—N(O)_(n)R^(b)R^(c) (where n is 0 or 1 if R^(b) and R^(c) are bothindependently alkyl, cycloalkyl or cycloalkylalkyl, and 0 if not) and—S(O)_(n)R^(d) (where n is an integer from 0 to 2), with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom, wherein R^(a) is hydrogen, acyl, alkoxycarbonyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl,cycloalkylalkyl, alkylsulfonyl, aminosulfonyl, mono- ordi-alkylaminosulfonyl, aminoalkyl, mono- or di-alkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl;and when n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, cycloalkylalkylor optionally substituted phenyl, and when n is 1 or 2, R^(d) is alkyl,cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino,acylamino, monoalkylamino, or dialkylamino. Representative examplesinclude, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

[0053] “Heteroalkylcarbonyl” means the group R_(a)—C(═O)—, where R_(a)is a heteroalkyl group. Representative examples includeacetyloxymethylcarbonyl, aminomethylcarbonyl,4-acetyloxy-2,2-dimethyl-butan-2-oyl, 2-amino-4-methyl-pentan-2-oyl, andthe like.

[0054] “Heteroalkyloxy” means the group R_(a)O—, where R_(a) is aheteroalkyl group. Representative examples include (Me—C(═O)—O—CH₂—O—,and the like

[0055] “Heteroalkyloxycarbonyl” means the group R_(a)C(═O), where R_(a)is a heteroalkyloxy group. Representative examples include1-acetyloxy-methoxycarbonyl (Me—C(═O)—O—CH₂—O—C(═O)—) and the like

[0056] “Heteroaryl” means a monovalent monocyclic or bicyclic radical of5 to 12 ring atoms having at least one aromatic ring containing one,two, or three ring heteroatoms selected from N, O, or S, the remainingring atoms being C, with the understanding that the attachment point ofthe heteroaryl radical will be on an aromatic ring. The heteroaryl ringis optionally substituted independently with one or more substituents,preferably one or two substituents, selected from alkyl, haloalkyl,heteroalkyl, hydroxy, alkoxy, halo, nitro or cyano. More specificallythe term heteroaryl includes, but is not limited to, pyridyl, furanyl,thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl,isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl,imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl, and the derivativesthereof.

[0057] “Heteroaralkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heteroaryl group as defined herein, e.g.,pyridin-3-ylmethyl, imidazolylethyl, pyridinylethyl,3-(benzofuran-2-yl)propyl, and the like.

[0058] “Heteroalkylsubstituted cycloalkyl” means a cycloalkyl radical asdefined herein wherein one, two or three hydrogen atoms in thecycloalkyl radical have been replaced with a heteroalkyl group with theunderstanding that the heteroalkyl radical is attached to the cycloalkylradical via a carbon-carbon bond. Representative examples include, butare not limited to, 1-hydroxymethylcyclopentyl,2-hydroxymethylcyclohexyl, and the like.

[0059] “Heterosubstituted cycloalkyl” means a cycloalkyl radical asdefined herein wherein one, two or three hydrogen atoms in thecycloalkyl radical have been replaced with a substituent independentlyselected from the group consisting of hydroxy, alkoxy, amino, acylamino,monoalkylamino, dialkylamino, oxo (C═O), imino, hydroximino (═NOH),NR′SO₂R^(d) (where R′ is hydrogen or alkyl and R^(d) is alkyl,cycloalkyl, hydroxyalkyl, amino, monoalkylamino or dialkylamino),—X—Y—C(O)R (where X is O or NR¹, Y is alkylene or absent, R is hydrogen,alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino, oroptionally substituted phenyl, and R¹ is H or alkyl), or —S(O)_(n)R(where n is an integer from 0 to 2) such that when n is 0, R ishydrogen, alkyl, cycloalkyl, cycloalkylalkyl optionally substitutedphenyl or thienyl, and when n is 1 or 2, R is alkyl, cycloalkyl,cycloalkylalkyl, optionally substituted phenyl, thienyl, amino,acylamino, monoalkylamino or dialkylamino. Representative examplesinclude, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, 2-, 3-,or 4-aminocyclohexyl, 2-, 3-, or 4-methanesulfonamido-cyclohexyl, andthe like, preferably 4-hydroxycyclohexyl, 2-aminocyclohexyl or4-methanesulfonamido-cyclohexyl.

[0060] “Heterosubstituted cycloalkyl-alkyl” means a radical R^(a)R^(b)—where R^(a) is a heterosubstituted cycloalkyl radical and R^(b) is analkylene radical.

[0061] “Heterocycloamino” means a saturated monovalent cyclic group of 4to 8 ring atoms, wherein one ring atom is N and the remaining ring atomsare C. Representative examples include piperidine and pyrrolidine.

[0062] “Heterocyclyl” means a saturated or unsaturated non-aromaticcyclic radical of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)_(n) (where n is an integer from0 to 2), the remaining ring atoms being C, where one or two C atoms mayoptionally be replaced by a carbonyl group. The heterocyclyl ring may beoptionally substituted independently with one, two, or threesubstituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro,cyano, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino,aralkyl, —(X)_(n)—C(O)R (where X is O or NR′, n is 0 or 1, R ishydrogen, alkyl, haloalkyl, hydroxy (when n is 0), alkoxy, amino,monoalkylamino, dialkylamino, or optionally substituted phenyl, and R′is H or alkyl), -alkylene-C(O)R^(a) (where R^(a) is alkyl, OR or NR′R″and R is hydrogen, alkyl or haloalkyl, and R′ and R″ are independentlyhydrogen or alkyl), or —S(O)_(n)R (where n is an integer from 0 to 2)such that when n is 0, R is hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl,cycloalkylalkyl, amino, acylamino, monoalkylamino, dialkylamino orheteroalkyl. More specifically the term heterocyclyl includes, but isnot limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl,piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino,thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,4-(1,1-dioxo-tetrahydro-2H-thiopyranyl), pyrrolinyl, imidazolinyl,N-methanesulfonyl-piperidin-4-yl, and the derivatives thereof.

[0063] “Heterocyclylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heterocyclyl group as defined above, e.g.,tetrahydropyran-2-ylmethyl, 2- or3-piperidinylmethyl,3-(4-methyl-piperazin-1-yl)propyl and the like.

[0064] “(Heterocyclyl)(cycloalkyl)alkyl” means an alkyl radical whereintwo hydrogen atoms have been replaced with a heterocyclyl group and acycloalkyl group.

[0065] “(Heterocyclyl)(heteroaryl)alkyl” means an alkyl radical whereintwo hydrogen atoms have been replaced with a heterocycyl group and aheteroaryl group. “Heterocyclyl spiro cycloalkyl” means a spiro radicalconsisting of a cycloalkyl ring and a heterocyclic ring with each ringhaving 5 to 8 ring atoms and the two rings having only one carbon atomin common, with the understanding that the point of attachment of theheterocyclyl spiro cycloalkyl radical is via the cycloalkyl ring. Thespiro radical is formed when two hydrogen atoms from the same carbonatom of the cycloalkyl radical are replaced with a heterocyclyl group asdefined herein, and may be optionally substituted with alkyl, hydroxy,hydroxyalkyl, or oxo. Examples include, but are not limited to, forexample, 1,4-dioxaspiro[4.5]decan-8-yl, 1,3-diazaspiro[4.5]decan-8-yl,2,4-dione-1,3-diaza-spiro[4.5]decan-8-yl,1,5-dioxa-spiro[5.5]undecan-9-yl,(3-hydroxymethyl-3-methyl)-1,5-dioxa-spiro[5.5]undecan-9-yl, and thelike.

[0066] “Hydroxyalkyl” means an alkyl radical as defined herein,substituted with one or more, preferably one, two or three hydroxygroups, provided that the same carbon atom does not carry more than onehydroxy group. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly,as used herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

[0067] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halo (such as chloro,bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy(e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

[0068] “Monoalkylamino” means a radical -NHR where R an alkyl,hydroxyalkyl, cycloalkyl, or cycloalkylalkyl group as defined above,e.g., methylamino, (1-methylethyl)amino, hydroxymethylamino,cyclohexylamino, cyclohexylmethylamino, cyclohexylethylamino, and thelike.

[0069] “Optionally substituted phenyl” means a phenyl ring which isoptionally substituted independently with one or more substituents,preferably one or two substituents selected from the group consisting ofalkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro,cyano, amino, methylenedioxy, ethylenedioxy, and acyl.

[0070] “Pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

[0071] “Pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolainine, tromethamine,N-methylglucamine, and the like.

[0072] The terms “pro-drug” and “prodrug” are used interchangeablyherein and refer to any compound which releases an active parent drugaccording to Formula I or II in vivo when such prodrug is administeredto a mammalian subject. Prodrugs of a compound of Formula I or II areprepared by modifying one or more functional group(s) present in thecompound of Formula I or II in such a way that the modification(s) maybe cleaved in vivo to release the parent compound. Prodrugs includecompounds of Formula I or II wherein a hydroxy, amino, sulfhydryl,carboxy or carbonyl group in a compound of Formula I or II is bonded toany group that may be cleaved in vivo to regenerate the free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, esters (e.g., acetate, dialkylaminoacetates,formates, phosphates, sulfates, and benzoate derivatives) and carbamates(e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, estersgroups (e.g. ethyl esters, morpholinoethanol esters) of carboxylfunctional groups, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases,Schiff bases and enaminones of amino functional groups, oximes, acetals,ketals and enol esters of ketone and aldehyde functional groups incompounds of Formula I or II, and the like, See Bundegaard, H. “Designof Prodrugs” p1-92, Elesevier, New York-Oxford (1985).

[0073] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in T. W.Green and P. G. Futs, Protective Groups in Organic Chemistry, (Wiley,2^(nd) ed. 1991) and Harrison and Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996).Representative amino protecting groups include, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES),trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC),and the like. Representative hydroxy protecting groups include thosewhere the hydroxy group is either acylated or alkylated such as benzyl,and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers,trialkylsilyl ethers and allyl ethers.

[0074] “Treating” or “treatment” of a disease includes: (1) preventingthe disease, i.e., causing the clinical symptoms of the disease not todevelop in a mammal that may be exposed to or predisposed to the diseasebut does not yet experience or display symptoms of the disease; (2)inhibiting the disease, i.e., arresting or reducing the development ofthe disease or its clinical symptoms; or (3) relieving the disease,i.e., causing regression of the disease or its clinical symptoms.

[0075] “A therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

DETAILED DESCRIPTION

[0076] Though the broadest description of the invention is set forth inthe Summary of the Invention, particular aspects are set forth below.

[0077] One aspect of the present invention provides a compound ofFormula I:

[0078] where R¹, R³, W, Z, X¹ and Ar¹, are as defined above. 2

[0079] Preferably W is NR², more preferably NH.

[0080] Preferably, Z is N.

[0081] Preferably, X¹ is O or CH₂, more preferably O.

[0082] Preferably, Ar¹ is optionally substituted phenyl, optionallysubstituted furylor optionally substituted thienyl. More preferably, Ar¹is optionally substituted phenyl, particularly 2-substituted,4-substituted or 2,4-disubstituted. Still more preferably, Ar¹ ismonohalo-substituted phenyl (e.g. 2-chlorophenyl, 2-fluorophenyl or4-fluorophenyl), monoalkylphenyl (e.g. 2-methylphenyl),dihalo-substituted phenyl(e.g. 2,4-difluorophenyl), dialkylphenyl (e.g.2,4-dimethylphenyl or 2,6-dimethylphenyl), 2,4-disubstitutedphenyl (e.g.4-fluoro-2-4 methylphenyl, 2-fluoro-4-methylphenyl).

[0083] Preferably, R¹ is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl, heterocyclyl or heterocyclylalkyl. More preferably R¹ isheteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl or heterocyclyl. A particularly preferred examples of aheteroalkyl R¹ is hydroxyalkyl, e.g., (1-hydroxy-2-methyl)-prop-2-yl,1-hydroxy-pentan-2-yl, (S)-2-hydroxy-1,2-dimethyl-propyl,(R)-2-hydroxy-1,2-dimethyl-propyl, (S)-2-hydroxy-1-methyl-ethyl,1-hydroxymethyl-cyclopentan-1-yl and 2-hydroxy-2-methyl-propyl.Particularly preferred examples of heterocyclyl R¹ includetetrahydro-2H-pyran-4-yl, 1-(methylsulfonyl)piperidin-4-yl and1,1-dioxidotetrahydro-2H-thiopyran-4-yl. Specific examples of R¹ include4-hydroxycyclohexyl, tetrahydro-2H-pyran-4-yl,1-(methylsulfonyl)piperidin-4-yl, cyclopentyl,(S)-(2-hydroxy-1,2-dimethyl)propyl, 2,2-diethoxyethyl,2,2-dimethoxyethyl, 3-hydroxypyridin-2-yl,(S)-(1-hydroxymethyl-2-methyl)propyl,4-(2-(N,N-diethylamino)ethoxy)phenyl, benzyl, phenyl, butyl, dodecyl,2-hydroxyethyl, 3-methylbutyl, 2-methylpropyl,(2-hydroxy-1,1-dimethyl)ethyl, 2,3,-dihydroxypropyl, 3-hydroxypropyl,hexyl, pyridin-2-yl, 2-morpholinoethyl, 2-(piperidin-1-yl)ethyl,cyclohexylmethyl, 1-(hydroxymethyl)butyl, 4-fluorophenyl,cyclopropylmethyl, 2-methoxyethyl, 3-(N,N-dimethylamino)propyl,isopropyl, methyl, 2-morpholino-2-(pyridin-4-yl)ethyl, 3-furylmethyl,1-oxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1-phenylpropyl, phenethyl,4-(2-hydroxyethyl)phenyl, 3-(4-methylpiperazin-1-yl)propyl,4-hydroxybutyl, 3-morpholinopropyl, 3-(2-pyrrolidinon-1-yl)propyl,2-acetamidoethyl, 2-(pyridin-2-yl)ethyl, pentyl,2-(N,N-dimethylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl,3-(pyrrolidin-1-yl)propyl, ethyl, 5-methylpyridin-2-yl, propyl, methyl,cyclopropyl, (1-hydroxymethyl-3-methylthio)propyl,(1-hydroxymethyl)cyclpentyl, 1,1-dimethylpropyl, 3-ethoxy-3-oxo-propyl,(1-(piperidin-1-yl)cyclohexyl)methyl, 3-methoxypropyl, cylcobutyl,1-(oxo-ethoxymethyl)piperidin-4-yl, 4-methoxycyclohexyl,2-cyclohexylethyl, (2-methylthiazol-5-yl)methyl,imidazo[2,1-b]thiazol-6-ylmethyl, hydrogen, 4-phenylbutyl,2-(4-aminophenyl)ethyl, pyridin-3-yl, tetrahydro-2H-thiopyran-4-yl and(1-hydroxymethyl)butyl.

[0084] Preferably, R³ is alkyl, aryl, cycloalkyl or heteroalkyl, morepreferably methyl.

[0085] Another aspect of the invention provides compounds of Formula II.

[0086] or pharmaceutically acceptable salts thereof,

[0087] wherein:

[0088] Z is N or CH;

[0089] W is NR²;

[0090] X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S, or CR⁵R⁶ (whereR⁵ and R⁶ are independently hydrogen or alkyl) or C═O;

[0091] Ar¹ is aryl or heteroaryl;

[0092] R¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstitutedcycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl,—Y¹—C(O)—Y²—R¹¹ (where Y¹ and Y² are independently either absent or analkylene group and R¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy,amino, monoalkylamino or dialkylamino), (heterocyclyl)(cycloalkyl)alkylor (heterocyclyl)(heteroaryl)alkyl;

[0093] R² is hydrogen or alkyl;

[0094] R⁷ is hydrogen or alkyl; and

[0095] R⁸ and R⁹ are independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl,—C(O)—R⁸¹ (where R⁸¹is alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- anddi-alkylamino, arylamino or aryl(alkyl)amino) where R¹, R³, W, Z, X¹ andAr¹, are as defined above.

[0096] Preferably W is NR², more preferably NH.

[0097] Preferably, Z is N.

[0098] Preferably, X¹ is O or CH₂, more preferably O.

[0099] Preferably, Ar¹ is optionally substituted phenyl, optionallysubstituted furyl or optionally substituted thienyl. More preferably,Ar¹ is optionally substituted phenyl, particularly 2-substituted,4-substituted or 2,4-disubstituted. Still more preferably, Ar¹ ismonohalo-substituted phenyl (e.g. 2-chlorophenyl, 2-fluorophenyl or4-fluorophenyl), monoalkylphenyl (e.g. 2-methylphenyl),dihalo-substituted phenyl(e.g. 2,4-difluorophenyl), dialkylphenyl (e.g.2,4-dimethylphenyl or 2,6-dimethylphenyl), 2,4-disubstitutedphenyl (e.g.4-fluoro-2-methylphenyl, 2-fluoro-4-methylphenyl).

[0100] Preferably, R¹ is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl, heterocyclyl or heterocyclylalkyl. More preferably R¹ isheteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl, or heterocyclyl.

[0101] Specific examples of R¹ include 4-hydroxycyclohexyl,tetrahydro-2H-pyran-4-yl, 1-(methylsulfonyl)piperidin-4-yl, cyclopentyl,(S)-(2-hydroxy-1,2-dimethyl)propyl, 2,2-diethoxyethyl,2,2-dimethoxyethyl, 3-hydroxypyridin-2-yl,(S)-(1-hydroxymethyl-2-methyl)propyl,4-(2-(N,N-diethylamino)ethoxy)phenyl, benzyl, phenyl, butyl, dodecyl,2-hydroxyethyl, 3-methylbutyl, 2-methylpropyl,(2-hydroxy-1,1-dimethyl)ethyl, 2,3,-dihydroxypropyl, 3-hydroxypropyl,hexyl, pyridin-2-yl, 2-morpholinoethyl, 2-(piperidin-1-yl)ethyl,cyclohexylmethyl, 1-(hydroxymethyl)butyl, 4-fluorophenyl,cyclopropylmethyl, 2-methoxyethyl, 3-(N,N-dimethylamino)propyl,isopropyl, methyl, 2-morpholino-2-(pyridin-4-yl)ethyl, 3-furylmethyl,1-oxidotetrahydro-2H-thiopyran-4-yl, 1-phenylpropyl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl, phenethyl,4-(2-hydroxyethyl)phenyl, 3-(4-methylpiperazin-1-yl)propyl,4-hydroxybutyl, 3-morpholinopropyl, 3-(2-pyrrolidinon-1-yl)propyl,2-acetamidoethyl, 2-(pyridin-2-yl)ethyl, pentyl,2-(N,N-dimethylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl,3-(pyrrolidin-1-yl)propyl, ethyl, 5-methylpyridin-2-yl, propyl, methyl,cyclopropyl, (1-hydroxymethyl-3-methylthio)propyl,(1-hydroxymethyl)cyclpentyl, 1,1-dimethylpropyl, 3-ethoxy-3-oxo-propyl,(1-(piperidin-1-yl)cyclohexyl)methyl, 3-methoxypropyl, cylcobutyl,1-(oxo-ethoxymethyl)piperidin-4-yl, 4-methoxycyclohexyl,2-cyclohexylethyl, (2-methylthiazol-5-yl)methyl,imidazo[2,1-b]thiazol-6-ylmethyl, hydrogen, 4-phenylbutyl,2-(4-aminophenyl)ethyl, pyridin-3-yl, tetrahydro-2H-thiopyran-4-yl and(1-hydroxymethyl)butyl.

[0102] The compounds of the present invention can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention. In addition to the compounds described above, thecompounds of the present invention include all tautomeric forms.Furthermore, the present invention also includes all pharmaceuticallyacceptable salts of those compounds along with prodrug forms of thecompounds and all stereoisomers whether in a pure chiral form or aracemic mixture or other form of mixture.

[0103] The compounds of Formula I and II are capable of further formingpharmaceutically acceptable acid addition salts. All of these forms arewithin the scope of the present invention.

[0104] Pharmaceutically acceptable acid addition salts of the compoundsof Formula I and II include salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M., et al., “PharmaceuticalSalts,” J. of Pharmaceutical Science, 1977, 66, 1-19).

[0105] The acid addition salts of the basic compounds can be prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formcan be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

[0106] Another aspect of the invention provides intermediates of FormulaI′ and II″, useful in preparing compounds of Formula I and II.

[0107] wherein:

[0108] Z is N or CH;

[0109] W is S, S(O), S(O)₂ or O;

[0110] X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S, or CR⁵R⁶ (whereR⁵ and R⁶ are independently hydrogen or alkyl) or C═O;

[0111] X² is O or NR⁷;

[0112] Ar¹ is aryl or heteroaryl;

[0113] R¹⁰ is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl, orR¹⁰W together form a leaving group or hydroxy;

[0114] R³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R³¹ (whereR³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino ordialkylamino), amino, monoalkylamino, dialkylamino or NR³²—Y³—R³³ (whereY³ is —C(O), —C(O)O—, —C(O)NR³, S(O)₂, or S(O)₂NR³⁵; R³², R³¹ and R³⁴are independently hydrogen or alkyl; and R³³ is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substitutedphenyl) or acyl;

[0115] R⁷ is hydrogen or alkyl; and

[0116] R⁸ and R⁹ are independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl,—C(O)—R⁸¹ (where R⁸¹is alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- anddi-alkylamino, arylamino or aryl(alkyl)amino) or R ⁸ and R⁹ togetherform ═CR⁸²R⁸³ (where R⁸³ and R⁸³ are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl or optionally substituted phenyl).

[0117] Compounds of Formula I″ and II″ where W is O can be prepared byhydrolyzing precursor sulfones such as If, 2e, IIIg shown in thefollowing Schemes 1-4 in refluxing aqueous acetic acid or aqueoushydroxide to provide a hydroxyl compound (i.e., compounds I′ and II″,wherein R¹⁰W is hydroxy). The resulting hydroxyl compound can bealkylated with R¹⁰—L where L is a leaving group to provide compounds ofFormula I′ and II″, where W is O and R¹⁰ is as described. Alternatively,the sulfone group in the precursor sulfone may be directly displacedwith an alcohol R¹⁰—OH as described in WO 96/33798 to provide compoundsof Formula I and II where W is O and R¹⁰ is as described. Compounds ofFormula I′ and II″ where R¹⁰W form a leaving group such as halo may beprepared by treating the precursor compound where R¹⁰W is hydroxy with ahalogenating agent such as phosphorous oxychloride or phosphorousoxybromide. Compounds of Formula I′ and II″ where R¹⁰W form a leavinggroup such as acetoxy, tosyloxy etc. may be prepared by treating theprecursor compound where R¹⁰W is hydroxy with an acylating orsulfonylating agent respectively.

[0118] While the forms of the invention herein constitute presentlypreferred embodiments, many others are possible. It is not intendedherein to mention all of the possible equivalent forms or ramificationsof the invention. It is understood that the terms used herein are merelydescriptive rather than limiting, and that various changes can be madewithout departing from the spirit or scope of the invention.

[0119] Processes for Preparing the Compounds

[0120] The compounds of the present invention can be prepared by avariety of methods. In one aspect of the present invention, a method forpreparing compounds of Formula I where Z is N is shown in Scheme 1below. It should be appreciated that although the scheme often indicatesexact structures, methods of the present invention apply widely toanalogous compounds of Formula I or II, given appropriate considerationto protection and deprotection of reactive functional groups by methodsstandard to the art of organic chemistry. For example, hydroxy groups,in order to prevent unwanted side reactions, sometimes need to beconverted to ethers or esters during chemical reactions at other sitesin the molecule. The hydroxy protecting group is then removed to providethe free hydroxy group. Similarly, amino groups and carboxylic acidgroups can be derivatized to protect them against unwanted sidereactions. Typical protecting groups, and methods for attaching andcleaving them, are described fully in the above incorporated referencesby T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, New York, 1999, andHarrison and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8 (John Wiley and Sons, 1971-1996).

[0121] Treatment of a compound of Formula Ia with a primary amine(R³—NH₂) provides a compound of Formula Ib. This reaction isconveniently carried out in a solvent which is inert under the reactionconditions, preferably a halogenated aliphatic hydrocarbon, especiallydichloromethane, an optionally halogenated aromatic hydrocarbon, or anopen-chain or cyclic ether such as tetrahydrofuran, a formamide or alower alkanol. Suitably, the reaction is carried out at about −20°C. toabout 120° C.

[0122] Reduction of a compound of Formula Ib provides alcohol of FormulaIc. This reduction is typically carried out using lithium aluminumhydride in a manner well known to those of skill in the art (e.g., in asolvent which is inert under the conditions of the reduction, preferablyan open-chain or cyclic ether, especially tetrahydrofuran, at about−20°°C. to about 70° C., preferably at about 0° C. to about roomtemperature).

[0123] Oxidation of an alcohol of Formula Ic provides a carboxaldehydeof Formula Id. The oxidation is typically carried out with manganesedioxide, although numerous other methods can also be employed (see, forexample, ADVANCED ORGANIC CHEMISTRY, 4^(th) ED., March, John Wiley &Sons, New York (1992)). Depending on the oxidizing agent employed, thereaction is carried out conveniently in a solvent which is inert underthe specific oxidation conditions, preferably a halogenated aliphatichydrocarbon, especially dichloromethane, or an optionally halogenatedaromatic hydrocarbon. Suitably, the oxidation is carried out at about 0°C. to about 60° C.

[0124] Reaction of a carboxaldehyde of Formula Id with an ester,Ar¹—X¹CH₂—CO₂R′ (where R′ is an alkyl group, and Ar¹ and X¹ are thosedefined above) in the presence of a base provides a compound of FormulaIe. Any relatively non-nucleophilic base can be used includingcarbonates, such as potassium carbonate, lithium carbonate, and sodiumcarbonate; bicarbonates, such as potassium bicarbonate, lithiumbicarbonate, and sodium bicarbonate; amines, such as secondary andtertiary amines; and resin bound amines such as 1,3,4,6,7,8-hexahydro-2Hpyrimido[1,2-a]pyrimidine. Conveniently, the reaction is carried out ina solvent which is relatively polar but inert under the reactionconditions, preferably an amide such as dimethyl formamide,N-substituted pyrrolidinone, especially 1-methyl-2-pyrrolidinone, and ata temperature of about 25° C. to about 150° C.

[0125] Oxidation of Ie with an oxidizing agent, e.g. a peracid such as3-chloroperbenzoic acid (i.e., MCPBA) or Oxone®, provides a sulfone (If)which can be converted to a variety of target compounds. Typically theoxidation of Ie is carried out in a solvent which is inert under theconditions of the oxidation. For example, when MCPBA is used as theoxidizing agent, the solvent is preferably a halogenated aliphatichydrocarbon, especially chloroform. When Oxone® is used as the oxidizingagent, the solvent is preferably methanol, aqueous ethanol or aqueoustetrahydrofuran. The reaction temperature depends on the solvent used.For an organic solvent, the reaction temperature is generally at about−20° C. to about 50° C., preferably about 0° C. to about roomtemperature. When water is used as the solvent, the reaction temperatureis generally from about 0° C. to about 50° C., preferably about 0° C. toabout room temperature. Alternatively, the oxidation may be carriedunder catalytic conditions with rhenium/peroxide based reagents, see(“Oxidation of Sulfoxides by Hydrogen Peroxide, Catalyzed byMethyltrioxorhenium(VII)”, Lahti, David W.; Espenson, James H, Inorg.Chem. (2000) 39(10) pp.2164-2167; “Rhenium oxo complexes in catalyticoxidations, Catal. Today (2000) 55(4), pp317-363 and “A Simple andEfficient Method for the Preparation of Pyridine N-Oxides”, Coperet,Christophe; Adolfsson, Hans; Khuong, Tinh-Alfredo V.; Yudin, Andrei K.;Sharpless, K. Barry, J. Org. Chem. (1998) 63(5), pp1740-1741).

[0126] Reacting the compound If with an amine (R¹—NH₂) provides thecompounds of Formula I′ (i.e., compounds I, wherein W is NH). Furtheralkylation of I′ then provides compounds of Formula I, where W is NR²,where R² is alkyl. The reaction can be carried out in the presence orabsence of solvent. Conveniently, the reaction is carried out attemperatures of from about 0° C. to about 200° C., more preferably aboutroom temperature to about 150° C. Alternatively, in some cases ratherthan using the sulfone If, the sulfide Ie or the corresponding sulfoxidecan be reacted directly with an amine (R¹—NH₂) to provide the compoundsof Formula I′.

[0127] Accordingly, the present invention provides a method of preparingcompounds of Formula I, by treating a compound of general Formula Ie, Ifor the corresponding sulfoxide with an amine (R¹—NH₂) and optionallyreacting the resulting product with R²—L, where R² is is alkyl and L isa leaving group.

[0128] Compounds of Formula I where R³ is amino, monoalkylamino,dialkylamino or NR²—Y³—R³³ may be prepared as shown in Scheme 2 from thecorresponding 2-alkylthio-8-amino-[2,3-d]pyridopyrimidin-7(8H)-one (IV,Z═N) or 7-alkylthio-1-amino-1,6-naphthyridin-2-one (IV, Z═CH) shown inScheme 2 by amination with O-diphenylphosphinylhydroxylamine.

[0129] Displacement of the sulfide (or the corresponding sulfoxide orsulfone with an amine R¹NH₂ as previously described for compound Ie inScheme 1 provides compounds of Formula I (compounds of Formula I where Zis CH and R² is H). Reacting the resulting product with R²—L, where R²is is alkyl and L is a leaving group gives compounds of Formula I whereR² is alkyl

[0130] Compounds of Formula I where Z is CH may be prepared as shown inScheme 3.

[0131] 4-amino-3,6-dibromo-pyridine (Den Hertog et. al., Rec. Trav.Chim. Pays-Bas, 64 85-100 (1945) is treated with sodium methyl thiolateto give 4-amino-3-bromo-6-methylthio-pyridine (Step a, see Windscheif,P; Voegtle, F.; Synthesis, 87092 (1994)._The methylthiopyridine iscoupled in a Heck reaction under palladium catalysis (e.g. palladiumacetate) in the presence of base (e.g. potassium acetate ortributylamine) with the vinyl ester 2a to give a compound of Formula 2b(see Dong, Y.; Busacca, C. A. J. Org. Chem., 62, 6464-65 (1997). Ringclosure under basic conditions gives a 1,6-naphthyridone of Formula 2c.Alkylation of 2c with an alkyl halide (or any other alkylating agentR³—X where X is a leaving group) gives a 1-alkylated naphthyridone ofFormula 2d. Oxidation of 2d and displacement of the sulfone with anamine R¹NH₂ as previously described for compound Ie in Scheme 1 providescompounds of Formula I″ (compounds of Formula I where Z is CH and R² isH). Reacting the resulting product with R²-L, where R² is is alkyl and Lis a leaving group gives compounds of 2 Formula I where R² is alkyl. Analternative route is shown in Scheme 3A.

[0132] Compounds of Formula II may be prepared as shown in Scheme 4.

[0133] Reaction of a carboxaldehyde of Formula Id (R³ is H) with anitrile, Ar¹—X¹CH₂—CN (where Ar¹ and X¹ are those defined above) in thepresence of a base under condtions similar to those described forconversion of Id to Ie in Scheme 1 provides a compound of Formula IIIe.Compounds of Formula IIIe may be sequentially alkylated, acylated orsulfonylated with alkylating agents, acyl halides, isocyanates,anhydrides and sulfonyl halides to provide compounds of Formula IIIfwhere R⁸ and R⁹ are as described in the Summary of the Invention.Subsequent oxidation of IIIf and displacement of the sulfone with anamine R¹NH₂ as previously described for compound Ie in Scheme 1 providescompounds of Formula III′. Further reacting the resulting product withR²—L, where R² is is alkyl and L is a leaving group gives compounds ofFormula II where R² is alkyl.

[0134] One of skill in the art will understand that certainmodifications to the above schemes are contemplated and within the scopeof the present invention. For example, certain steps will involve theuse of protecting groups for functional groups that are not compatiblewith particular reaction conditions.

[0135] Pharmaceutical Compositions Containing the Compounds

[0136] The compounds of Formula I and II and the pharmaceuticallyacceptable salts of basic compounds of Formula I and II with acids canbe used as medicaments, e.g., in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredenterally, e.g., orally in the form of tablets, coated tablets, dragees,hard and soft gelatine capsules, solutions, emulsions or suspensions,nasally, e.g., in the form of nasal sprays, or rectally, e.g., in theform of suppositories. However, they may also be administeredparenterally, e.g., in the form of injection solutions.

[0137] The compounds of Formula I and II and their aforementionedpharmaceutically acceptable salts can be processed with pharmaceuticallyinert, organic or inorganic carriers for the production ofpharmaceutical preparations. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragees and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like; depending on the nature of the active ingredient no carriersare, however, usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar, glucose and the like.Suitable carriers for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0138] The pharmaceutical preparations can also contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain therapeuticallyvaluable substances other than the compounds of Formula I and II andtheir aforementioned pharmaceutically acceptable salts.

[0139] Medicaments which contain a compound of Formula I or II or apharmaceutically acceptable salt of a basic compound of Formula I or IIwith an acid in association with a compatible pharmaceutical carriermaterial are also an object of the present invention, as is a processfor the production of such medicaments which comprises bringing one ormore of these compounds or salts and, if desired, one or more othertherapeutically valuable substances into a galenical administration formtogether with a compatible pharmaceutical carrier.

[0140] As mentioned earlier, the compounds of Formula I and II and theiraforementioned pharmaceutically acceptable salts can be used inaccordance with the invention as therapeutically active substances,especially as antiinflammatory agents or for the prevention of graftrejection following transplant surgery. The dosage can vary within widelimits and will, of course, be fitted to the individual requirements ineach particular case. In general, in the case of administration toadults a convenient daily dosage should be about 0.1 mg/kg to about 100mg/kg, preferably about 0.5 mg/kg to about 5 mg/kg. The daily dosage maybe administered as a single dose or in divided doses and, in addition,the upper dosage limit referred to earlier may be exceeded when this isfound to be indicated.

[0141] Finally, the use of compounds of Formula I and II and theiraforementioned pharmaceutically acceptable salts for the production ofmedicaments, especially in the treatment or prophylaxis of inflammatory,immunological, oncological, bronchopulmonary, dermatological andcardiovascular disorders, in the treatment of asthma, central nervoussystem disorders or diabetic complications or for the prevention ofgraft rejection following transplant surgery, is also an object of theinvention.

[0142] Methods of Using the Compounds and Compositions

[0143] Compounds of Formula I and II would be useful for, but notlimited to, the treatment of any disorder or disease state in a human,or other mammal, which is exacerbated or caused by excessive orunregulated TNF or p38 kinase production by such mammal. Accordingly,the present invention provides a method of treating a cytokine-mediateddisease which comprises administering an effective cytokine-interferingamount of a compound of Formula I, or a pharmaceutically acceptable saltor tautomer thereof.

[0144] Compounds of Formula I and II would be useful for, but notlimited to, the treatment of inflammation in a subject, and for use asantipyretics for the treatment of fever. Compounds of the inventionwould be useful to treat arthritis, including but not limited to,rheumatoid arthritis, spondyloarthropathies, gouty arthritis,osteoarthritis, systemic lupus erythematosus and juvenile arthritis,osteoarthritis, gouty arthritis and other arthritic conditions. Suchcompounds would be useful for the treatment of pulmonary disorders orlung inflammation, including adult respiratory distress syndrome,pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonaryinflammatory disease. The compounds are also useful for the treatment ofviral and bacterial infections, including sepsis, septic shock, gramnegative sepsis, malaria, meningitis, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes virus.The compounds are also useful for the treatment of bone resorptiondiseases, such as osteoporosis, endotoxic shock, toxic shock syndrome,reperfusion injury, autoimmune disease including graft vs. host reactionand allograft rejections, cardiovascular diseases includingatherosclerosis, thrombosis, congestive heart failure, and cardiacreperfusion injury, renal reperfusion injury, liver disease andnephritis, and myalgias due to infection.

[0145] The compounds are also useful for the treatment of Alzheimer'sdisease, influenza, multiple sclerosis, cancer, diabetes, systemic lupuserthrematosis (SLE), skin-related conditions such as psoriasis, eczema,burns, dermatitis, keloid formation, and scar tissue formation. Inaddition, compounds of the invention are useful in treatinggastrointestinal conditions such as inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome and ulcerative colitis. Thecompounds are also useful in the treatment of ophthalmic diseases, suchas retinitis, retinopathies, uveitis, ocular photophobia, and of acuteinjury to the eye tissue. The compounds can also be used in treatingangiogenesis, including neoplasia; metastasis; ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemangiomas,including infantile hemangiomas, angiofibroma of the nasopharynx andavascular necrosis of bone; diabetic nephropathy and cardiomyopathy; anddisorders of the female reproductive system such as endometriosis. Thecompounds can further be used for preventing the production ofcyclooxygenase-2.

[0146] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0147] The present compounds can also be used in co-therapies, partiallyor completely, in place of other conventional antiinflammatories, suchas together with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS,immunosuppressive agents, 5-lipoxygenase inhibitors, LTB₄ antagonistsand LTA₄ hydrolase inhibitors.

[0148] As used herein, the term “TNF mediated disorder” refers to anyand all disorders and disease states in which TNF plays a role, eitherby control of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disorder mediated by TNF.

[0149] As used herein, the term “p38 mediated disorder” refers to anyand all disorders and disease states in which p38 plays a role, eitherby control of p38 itself, or by p38 causing another factor to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to p38, wouldtherefore be considered a disorder mediated by p38.

[0150] As TNF-β has close structural homology with TNF-α (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, the synthesis of both TNF-α and TNF-β areinhibited by the compounds of the present invention and thus are hereinreferred to collectively as “TNF” unless specifically delineatedotherwise.

EXAMPLES

[0151] Additional objects, advantages, and novel features of thisinvention will become apparent to those skilled in the art uponexamination of the following illustrative examples thereof, which arenot intended to be limiting.

[0152] Unless otherwise stated, all temperatures including meltingpoints (i.e., Mpt.) are in degrees celsius (° C.).

Example 1 Preparation of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde

[0153]

[0154] Step A: Preparation of Ethyl4-methylamino-2-methyl-thiopyrimidine-5-carboxylate

[0155] To a solution of ethyl4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 20 g, 86 mmol)in 250 mL of dichworomethane at 0° C. was added slowly solution ofmethylamine in ethanol (33%, 35 mL 281 mmol). After stirring for 30minutes, water (150 mL) was added and the phases were separated. Theorganic phase was dried (MgSO₄) and filtered. The filtrate wasevaporated under reduced pressure to give 19 g of the ethyl4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.

[0156] Step B: Preparation of4-methylamino-2-methylthiopyrimidine-5-methanol

[0157] Lithium aluminum hydride (8.2 g, 215 mmol) was stirred in drytetrahydrofuran (300 mL) at 5° C. and treated dropwise with a solutionof ethyl 4-methylamino-2-methylthio-pyrimidine-5-carboxylate (46 g, 215mmol) in dry tetrahydrofuran (450 mL). The reaction mixture was stirredfor 15 minutes and then water (18 mL) was added dropwise with caution.The reaction was stirred for 30 minutes and then an aqueous solution ofsodium hydroxide (15%, 8.5 mL) was added dropwise, followed by water(25.5 mL). The resulting suspension was stirred for 17 hours at roomtemperature and then filtered. The filter residue was washed withtetrahydrofuran (2×, 100 mL) and the combined filtrate and washings wereevaporated under reduced pressure. The residue was suspended in ethylacetate/hexane −½ (200 mL) and the solid was filtered and dried toprovide 32.7 g of 4-methylamino-2-methylthiopyrimidine-5-methanol as ayellow solid.

[0158] Step C: Preparation of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde

[0159] 4-Methylamino-2-methylthiopyrimidine-5-methanol (20 g, 108 mmol)and 1 L of dichioromethane were combined with stirring and treated withmanganese dioxide (87 g, 1 mol). The resulting suspension was stirredfor 24 hours and then filtered through celite. The filter residue waswashed with dichloromethane (100 mL) and the combined filtrate andwashings were evaporated under reduced pressure to give 15.8 g of the4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde as a white solid.

Example 2 Preparation of 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde

[0160]

[0161] The 4-cyclopropylamino-2-methylthiopyrimidine-5-carboxaldehydewas prepared as described in Example 1 (steps A through C) starting withethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich ChemicalCo.) and cyclopropyl amine (Aldrich Chemical Co.).

Example 3 Preparation of 4-[(4-fluorophenyl)amino]-2-(methylthio)pyrimidine-5-carboxaldehyde

[0162]

[0163] The4-[(4-fluorophenyl)amino]-2-(methylthio)pyrimidine-5-carbaldehyde wasprepared as described in Example 1 (steps A through C) starting withethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich ChemicalCo.) and 4-fluoroaniline (Aldrich Chemical Co.).

Example 4 Preparation of methyl 2-fluorophenoxyacetate

[0164]

[0165] To a solution of 2-fluorophenol (6.72 g, 60 mmol) in 50 mL of1-methyl-2-pyrrolidinone was added methyl bromoacetate (6.24 mL, 65.92mmol) and potassium carbonate (9.9 g, 72 mmol). The reaction was stirredfor 12 hours at room temperature and then poured into water. The aqueoussolution was extracted with ethyl acetate, washed with water and dried(brine, Na₂SO₄). Evaporation of organic solvents yielded 10.5 g of therespective acetate (spectral data matched that of known literaturecompound).

Example 5 Preparation of Methyl (phenylthio)acetate

[0166]

[0167] To a solution of thiophenol (1.09 g, 9.9 mmol) in 25 mL of1-methyl-2-pyrrolidinone was added methyl bromoacetate (1.1 mL, 12 mmol)and potassium carbonate (2.0 g, 14.5 mmol). The reaction was stirred for12 hours at room temperature and then poured into water. The aqueoussolution was extracted with ethyl acetate, washed with water and dried(brine, Na₂SO₄). Evaporation of organic solvents yielded 1.2 g of therespective acetate (spectral data matched that of known literaturecompound).

Example 6 Preparation of Ethyl 3-(2-fluorophenyl)propanoate

[0168]

[0169] Step A:

[0170] To a solution of (2E)-3-(2-fluorophenyl)prop-2-enoic acid (10.0g, 9.9 mmol) in 100 mL of EtOH was added sulfuric acid (0.2 mL). Thereaction was refluxed for 5 hours and then cooled to room temperature.The reaction solution was evaporated to ¼ of the original volume andpoured into water. Extraction of the mixture with ethyl acetate followedby drying (brine, Na₂SO₄) and complete evaporation yielded the esterwhich was taken on the Step B.

[0171] Step B:

[0172] The ester (Step A) was dissolved in 50 mL of ethanol and acatalytic amount of palladium on carbon was added. The reaction washydrogenated in a Parr hydrogenator for 6 hours at room temperature.Filtration of the reaction mixture through a celite pad, followed byevaporation of the solvent under reduced pressure yielded 9.8 g of thefluoropropanoate (spectral data matched that of known literaturecompound).

Example 7 Preparation of 6-phenoxy-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 1)

[0173]

[0174] Step A: Preparation of6-phenoxy-8-methyl-2-(thiomethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0175] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (10 g, 54.6 mmol)and methyl phenoxyacetate (Aldrich, 11.4 g, 68.6 mmol) in 150 mL of1-methyl-2-pyrrolidinone was added potassium carbonate (14 g, 101.4mmol). The reaction mixture was heated to 120° C. and after 12 hours,additional phenoxyacetate (3×, 6.0 g, 36.1 mmol) and potassium carbonate(6.0 g, 44 mmol) was added. After 6 hours of stirring at 120° C., thereaction was cooled to room temperature and water (300 mL) was added.The solution was stirred for 1 hour and filtered. The resultant solidwas chromatographed (SiO₂, EtOAC/Hexane-{fraction (50/50)} to EtOAc100%) and then isolated via evaporation of solvents yielding 5 g of thesulfide (mass spec. M+1=300).

[0176] Step B: Preparation of 6-phenoxy-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 1)

[0177] The sulfide (5.07 g, 17.8 mmol) was dissolved in 100 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 5.9 g, 24 mmol) wasadded. The mixture was stirred at room temperature for 12 to 16 hours,filtered and then washed with aqueous sodium sulfite solution (2×, 75mL) followed by saturated aqueous sodium bicarbonate solution (2×, 75mL). The organic solution was then dried (brine, Na₂SO₄) and evaporatedunder reduced pressure. The resultant solid was chromatographed (SiO₂,EtOAc/Hexane—80/20) and then isolated via evaporation of solventsyielding 3.0 g of the sulfone (mass spec. M+1=332).

Example 8 Preparation of 6-(2-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 2)

[0178]

[0179] Step A: Preparation of6-(2-fluorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0180] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26.2 mmol)and methyl 2-fluorophenoxyacetate (5.9 g, 32 mmol) in 50 mL of1-methyl-2-pyrrolidinone was added potassium carbonate (6.0 g, 43.5mmol). The reaction mixture was heated to 120° C. and after 12 hours,additional phenoxyacetate (2.0 g, 10.8 mmol) and potassium carbonate(2.0 g, 15 mmol) was added. After 6 hours of stirring at 120° C., thereaction was cooled to room temperature and water (700 mL) was added.The solution was stirred for 45 minutes and filtered. The resultantsolid was washed with water (2×, 100 mL) and added to ethyl acetate (100mL) and stirred for 1 hour. The solid was then isolated via filtrationand dried yielding 6.4 g of the sulfide (mass spec. M+1=318, MP=234-236°C.).

[0181] Step B: Preparation of6-(2-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 2)

[0182] The sulfide (6.3 g, 20.5 mmol) was dissolved in 50 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 9.9 g, 44.2 mmol)was added. The mixture was stirred at room temperature for 12 to 16hours, then washed with aqueous sodium sulfite solution (2×, 75 mL)followed by saturated aqueous sodium bicarbonate solution (3×, 75 mL).The organic solution was then dried (brine, Na₂SO₄) and evaporated. Theresultant solid was stirred with ether for 1 hour and filtered to yieldthe sulfone (mass spec. M+1=350, MP=158-162° C.).

Example 9 Preparation of 6-(3-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2.3-d]pyrimidin-7(8H)-one (Sulfone 3)

[0183]

[0184] Step A: Preparation of6-(3-fluorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0185] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 26.2mmol) and methyl 3-fluorophenoxyacetate (0.61 g, 3.3 mmol) in 5 mL of1-methyl-2-pyrrolidinone was added potassium carbonate (0.6 g, 4.3mmol). The reaction mixture was heated to 120° C. and after 12 hours,additional phenoxyacetate (0.3 g, 1.5 mmol) and potassium carbonate (0.4g, 2.9 mmol) was added. After 6 hours of stirring at 120° C., thereaction was cooled to room temperature and water (100 mL) was added.The reaction mixture was extracted with ethyl acetate (2×, 75 mL) andthe resultant organic solution was washed with water (5×, 50 mL) thendried (brine, MgSO₄). Evaporation of the solution yielded a solid whichwas recrystalized (EtOAc/Hexane) yielding 1.0 g of the sulfide (massspec. M+1=317).

[0186] Step B: Preparation of6-(3-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 3)

[0187] The sulfide (1.02 g, 3.2 mmol) was dissolved in 25 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 1.7 g, 9.6 mmol)was added. The mixture was stirred at room temperature for 16 hours,diluted with methylene chloride (25 mL) then washed with aqueous sodiumsulfite solution (3×, 50 mL) followed by saturated aqueous sodiumbicarbonate solution (3×, 50 mL). The organic solution was then dried(brine, MgSO₄) and evaporated to yield 0.64 g of the sulfone (mass spec.M+1=349).

Example 10 Preparation of6-(2,6-difluorophenoxy)-8-methyl-2-(methylsulfonylpyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 4)

[0188]

[0189] Step A: Preparation of6-(2,6-difluorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0190] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26.2 mmol)and methyl 2,6-difluorophenoxyacetate (prepared as in Example 4 using2,6-difluorophenol, 5.9 g, 32 mmol) in 50 mL of 1-methyl-2-pyrrolidinonewas added potassium carbonate (6.0 g, 43.5 mmol). The reaction mixturewas heated to 120° C. and after 12 hours, additional phenoxyacetate (2×,2.0 g, 10.8 mmol) and potassium carbonate (2.0 g, 15 mmol) was added.After 6 hours of stirring at 120° C., the reaction was cooled to roomtemperature and water (70 mL) was added. The solution was stirred for 30minutes and filtered. The resultant solid was washed with water (2×),ethyl acetate and ether. The solid was then dried yielding 7.0 g of thesulfide (mass spec. M+1=336, MP=247-250.7° C.).

[0191] Step B: Preparation of6-(2,6-difluorophenoxy)-8-methyl-2-(methylsulfonylpyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 4)

[0192] The sulfide (7.0 g, 20.8 mmol) was dissolved in 50 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 11.5 g, 51.5 mmol)was added. The mixture was stirred at room temperature for 16 hours,filtered then washed with aqueous sodium sulfite solution (2×, 75 mL)followed by saturated aqueous sodium bicarbonate solution (3×, 75 mL).The organic solution was then dried (brine, Na₂SO₄) and evaporated. Theresultant solid was stirred with ether for 1 hour and filtered to yield5.5 g of the sulfone (mass spec. M+1=368, MP=215.2-216.4° C.).

Example 11 Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Sulfone 5)

[0193]

[0194] Step A: Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0195] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26.2 mmol)and methyl 2,4-difluorophenoxyacetate (prepared as in Example 4 using2,4-difluorophenol, 5.4 g, 29 mmol) in 50 mL of 1-methyl-2-pyrrolidinonewas added potassium carbonate (6.0 g, 43.5 mmol). The reaction mixturewas heated to 120° C. and after 12 hours, additional phenoxyacetate (2.5g, 13.4 mmol) and potassium carbonate (2.5 g, 18 mmol) was added. After6 hours of stirring at 120° C., the reaction was cooled to roomtemperature and water (100 mL) was added. The solution was stirred for45 minutes and filtered. The resultant solid was washed with water (3×)and added to ethyl acetate (75 mL) and stirred for 1 hour. The solid wasthen isolated via filtration and dried yielding 6.1 g of the sulfide(mass spec. M+1=336, MP=175.2-176.9° C.).

[0196] Step B: Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Sulfone 5)

[0197] The sulfide (6.0 g, 20.5 mmol) was dissolved in 50 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 9.3 g, 41.5 mmol)was added. The mixture was stirred at room temperature for 16 hours,then washed with aqueous sodium sulfite solution (2×, 75 mL) followed bysaturated aqueous sodium bicarbonate solution (3×, 75 mL). The organicsolution was then dried (brine, Na₂SO₄) and evaporated. The resultantsolid was stirred with ether for 1 hour and filtered to yield thesulfone (mass spec. M+1=368, MP=177.2-178.5° C.).

Example 12 Preparation of6-(2-chlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Sulfone 6)

[0198]

[0199] Step A: Preparation of6-(2-chlorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0200] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (5.5 g, 30 mmol)and methyl 2-chlorophenoxyacetate (prepared as in Example 4 using2-chlorophenol, 7.0 g, 35 mmol) in 80 mL of 1-methyl-2-pyrrolidinone wasadded potassium carbonate (9.0 g, 65.2 mmol). The reaction mixture washeated to 120° C. and after 12 hours, additional phenoxyacetate (2×, 0.5g, 2.5 mmol) and potassium carbonate (2×, 2.0 g, 15 mmol) was added.After 6 hours of stirring at 120° C., the reaction was cooled to roomtemperature and water (100 mL) was added. The solution was stirred for45 minutes and filtered. The resultant solid was filtered and washedwith water (2×) and ether (2×). Drying of the product via vacuum ovenyielded 9.0 g of the sulfide (mass spec. M+1=334).

[0201] Step B: Preparation of6-(2-chlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Sulfone 6)

[0202] The sulfide (8.9 g, 26.7 mmol) was dissolved in 70 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 13 g, 58 mmol) wasadded. The mixture was stirred at room temperature for 16 hours,filtered then washed with aqueous sodium sulfite solution (2×, 75 mL)1followed by saturated aqueous sodium bicarbonate solution (3×, 75 mL).The organic solution was then dried (brine, Na₂SO₄) and evaporated. Theresultant solid was stirred with ether for 18 hours and filtered toyield 8.5 g of the sulfone (mass spec. M+1=366).

Example 13 Preparation of6-(4-chlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Sulfone 7)

[0203]

[0204] Step A: Preparation of6-(4-chlorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0205] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 3.0 mmol)and methyl 4-chlorophenoxyacetate (prepared as in Example 4 using4-chlorophenol, 0.66 g, 3.3 mmol) in 5 mL of 1-methyl-2-pyrrolidinonewas added potassium carbonate (0.5 g, 3.6 mmol). The reaction mixturewas heated to 120° C. and after 12 hours, additional phenoxyacetate (0.3g, 1.5 mmol) and potassium carbonate (0.4 g, 2.9 mmol) was added. After6 hours of stirring at 120° C., the reaction was cooled to roomtemperature and poured into water (100 mL). The reaction mixture wasextracted with ethyl acetate (2×, 75 mL) and the resultant organicsolution was washed with water (5×, 50 mL) then dried (brine, MgSO₄).Evaporation of the solution yielded a solid which was recrystalized(EtOAc/Hexane) yielding 0.55 g of the sulfide (mass spec. M+1=334).

[0206] Step B: Preparation of6-(4-chlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(Sulfone 7)

[0207] The sulfide (1.44 g, 4.3 mmol) was dissolved in 50 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 2.2 g, 12.8 mmol)was added. The mixture was stirred at room temperature for 16 hours,filtered then washed with aqueous sodium sulfite solution (3×, 75 mL)followed by saturated aqueous sodium bicarbonate solution (3×, 50 mL).The organic solution was then dried (brine, MgSO₄) and evaporated. Theresultant solid was stirred with ether for 18 hours and filtered toyield 0.7 g of the sulfone (mass spec. M+1=366).

Example 14 Preparation of 8-methyl-2-(methylthio)-6-(phenylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfide 1)

[0208]

[0209] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (549 mg, 3 mmol)and methyl (phenylthio)acetate (600 mg, 3.3 mmol) in 25 mL of1-methyl-2-pyrrolidinone was added potassium carbonate (750 mg, 5.4mmol). The reaction mixture was heated to 120° C. and after 12 hours, itwas cooled to room temperature and water (50 mL) was added. The aqueousmixture was extracted with ethyl acetate (75 mL) yielding a organicsolution which was washed with water (2×, 50 mL) and dried (brine,Na₂SO₄). Evaporation of the solvent yielded a solid which was stirredwith ether and hexane for 1 hour. Filtration of the solid yielded 0.67 gof the sulfide (mass spec. M+1=316).

Example 15 Preparation of 6-[(4-fluorophenyl)thiol-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfide 2)

[0210]

[0211] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 3 mmol)and methyl (4-fluorophenylthio)acetate (prepared as in Example 5 using4-fluorothiophenol, 0.65 g, 3.3 mmol) in 25 mL of1-methyl-2-pyrrolidinone was added1,3,4,6,7,8,-hexahydro-2H-pyrimido(1,2-a)pyrimidine polymer bound resinbase (Aldrich, 200 mg). The reaction mixture was heated to 120° C. After12 hours it was cooled to room temperature and added to water (50 mL).The aqueous mixture was extracted with ethyl acetate (75 mL) yielding aorganic solution which was washed with water (2×, 50 mL) and dried(brine, Na₂SO₄). Evaporation of the solvent yielded 0.95 g of thesulfide (mass spec. M+1=334).

Example 16 Preparation of 6-(2-fluorobenzyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 8)

[0212]

[0213] Step A: Preparation of 6-(2-fluorobenzyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0214] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26.2 mmol)and ethyl 3-(2-fluorophenyl)propanoate (5.7 g, 29 mmol) in 50 mL of1-methyl-2-pyrrolidinone was added potassium carbonate (6.0 g, 43.5mmol). The reaction mixture was heated to 120° C. and after 12 hours,additional propanoate (1.5 g, 7.6 mmol) and potassium carbonate (3.0 g,22 mmol) was added. After 6 hours of stirring at 120° C., the reactionwas cooled to room temperature and water (700 mL) was added. Thesolution was stirred for 45 minutes and filtered. The resultant solidwas washed with water (3×, 50 mL) and added to ethyl acetate (75 mL) andstirred for 1 hour. The solid was then isolated via filtration and driedyielding 7.5 g of the sulfide (mass spec. M+1=316, MP=156-159° C.).

[0215] Step B: Preparation of6-(2-fluorobenzyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 8)

[0216] The sulfide (7.4 g, 23.5 mmol) was dissolved in 50 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 11.5 g, 51 mmol)was added. The mixture was stirred at room temperature for 16 hours,filtered and then washed with aqueous sodium sulfite solution (2×, 75mL) followed by saturated aqueous sodium bicarbonate solution (3×, 75mL). The organic solution was then dried (brine, Na₂SO₄) and evaporated.The resultant solid was stirred with ether for 1 hour and filtered toyield the sulfone (mass spec. M=348, MP=153.8-154.4 ° C.).

Example 17 Preparation of 6-(4-fluorobenzyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 9)

[0217]

[0218] Step A: Preparation of 6-(4-fluorobenzyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0219] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26.2 mmol)and ethyl 3-(4-fluorophenyl)propanoate (prepared as in Example 6, 5.7 g,29 mmol) in 50 mL of 1-methyl-2-pyrrolidinone was added potassiumcarbonate (6.0 g, 43.5 mmol). The reaction mixture was heated to 120° C.and after 12 hours, additional propanoate (1.5 g, 7.6 mmol) andpotassium carbonate (3.0 g, 22 mmol) was added. After 6 hours ofstirring at 120° C., the reaction was cooled to room temperature andwater (100 mL) was added. The solution was stirred for 45 minutes andfiltered. The resultant solid was washed with water (2×) and thenisolated via filtration and dried yielding 6.5 g of the sulfide (massspec. M+1=316).

[0220] Step B: Preparation of6-(4-fluorobenzyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 9)

[0221] The sulfide (6.5 g, 20.6 mmol) was dissolved in 50 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 10.1 g, 45 mmol)was added. The mixture was stirred at room temperature for 16 hours,filtered and then washed with aqueous sodium sulfite solution (2×, 75mL) followed by saturated aqueous sodium bicarbonate solution (3×, 75mL). The organic solution was then dried (brine, Na₂SO₄) and evaporated.The resultant solid was stirred with ether for 1 hour and filtered toyield 6.7 g of the sulfone (mass spec. M+1=348).

Example 18 Preparation of 8-cyclopropyl-6-(2-fluorophenoxy)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 10)

[0222]

[0223] Step A: Preparation of8-cyclopropyl-6-(2-fluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0224] The cyclopropyl sulfide was prepared using the proceduredescribed in Example 8 (step A) starting with4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (Example2, 1.814 g, 8.67 mmol) and methyl 2-fluorophenoxyacetate (Example 4,1.756 g, 9.53 mmol). It was taken directly on to Step B.

[0225] Step B: Preparation of8-cyclopropyl-6-(2-fluorophenoxy)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 10)

[0226] The sulfide (3.02 g, 8.8 mmol) was dissolved in 50 mL oftetrahydrofuran, cooled to 0° C. and oxone (Aldrich, 10.8 g, 17.6 mmol)in 50 mL of water was added dropwise holding the temperature constant.After the addition was completed, the reaction mixture was allowed towarm to room temperature and stir for 4 hours. Water (50 mL) and ethylacetate (75 mL) were then added and the reaction was partitioned betweenthe two phases. The organic layer was dried (brine, MgSO₄) andevaporation of the solvent yielded 2.26 g of the sulfone (mass spec.M+1=376).

Example 19 Preparation of6-(2-fluorophenoxy)-8-(4-fluorophenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 11)

[0227]

[0228] Step A: Preparation of6-(2-fluorophenoxy)-8-(4-fluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0229] The fluorophenyl sulfide was prepared using the proceduredescribed in Example 8 (step A) starting with4-[(4-fluorophenyl)amino]-2-(methylthio) pyrimidine-5-carbaldehyde(Example 3, 1.22 g, 4.6 mmol) and methyl 2-fluorophenoxyacetate (Example4, 0.93 g, 5.7 mmol). It was taken directly on to Step B.

[0230] Step B: Preparation of6-(2-fluorophenoxy)-8-(4-fluorophenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Sulfone 11)

[0231] The sulfide (0.75 g, 1.88 mmol) was dissolved in 20 mL oftetrahydrofuran, cooled to 0° C. and oxone (Aldrich, 2.38 g, 3.88 mmol)in 20 mL of water was added dropwise holding the temperature constant.After the addition was completed, the reaction mixture was allowed towarm to room temperature and stir for 4 hours. Water (100 mL) and ethylacetate (100 mL) were then added and the reaction was partitionedbetween the two phases. The organic layer was dried (brine, MgSO₄) andevaporation of the solvent yielded 0.77 g of the sulfone (mass spec.M+1=414, MP=82.3-91.5° C.).

Example 20 Preparation of2-amino-6-(2-fluorophenoxy)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one

[0232]

[0233] A mixture of sulfone 2 (0.315 g, 0.9 mmol) and ammonia (0.5M in1,4-dioxane, 2 mL, 1 mmole) in 1 mL of 1-methyl-2-pyrrolidinone washeated to 80° C. for 4 hours under a nitrogen atmosphere. The reactionmixture was cooled, evaporated under reduced pressure and purified viacolumn chromatography (SiO₂, CH₂Cl₂/MeOH—99/1). Isolation of the productvia evaporation of solvents and drying provided 0.33 g of the amine(Mass spec. M+1=287, MP=240.8-242.6° C.).

Example 21 Preparation of6-(phenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0234]

[0235] A mixture of sulfone 1 (0.20 g, 0.6 mmol) and4-amino-tetrahydropyran (Combi-Blocks-vendor, 0.183 g, 1.81 mmol) in 0.2mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3 hours. Thereaction mixture was cooled, poured into water and extracted with ethylacetate (2×, 50 mL). The organic solution was washed with water (5×, 50mL) and dried (brine, MgSO₄). Evaporation of the solvent and addition ofmethanol followed by acidification (1M, HCL/Et₂O, 1.5 eq) yielded thehydrochloride salt which was isolated as a solid via filtration (0.166g, mass spec. M+1=353).

Example 22 Preparation of6-(3-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0236]

[0237] A mixture of sulfone 3 (0.20 g, 0.57 mmol) and4-amino-tetrahydropyran (Combi-Blocks-vendor, 0.173 g, 1.72 mmol) in 0.2mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3 hours. Thereaction mixture was cooled and methanol (0.2-0.5 mL) was added. Theproduct precipitated and was isolated via filtration. The yellow solidwas transferred to a flask with methanol (5 mL). Dropwise addition ofhydrochloric acid in ether (1M, 1.5 eq) followed by stirring for 15hours yielded the hydrochloride salt which was isolated as a solid(0.129 g, mass spec. M+1=371).

Example 23 Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0238]

[0239] A mixture of sulfone 5 (0.20 g, 0.54 mmol) and4-amino-tetrahydropyran (Combi-Blocks-vendor, 0.165 g, 1.63 mmol) in 0.3mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3 hours. Thereaction mixture was cooled, poured into water and extracted with ethylacetate (2×, 50 mL). The organic solution was washed with water (5×, 25mL) and dried (brine, MgSO₄). Evaporation of the solvent and addition ofmethanol followed by hydrochloric acid in ether (1M, 1.5 eq) yielded thehydrochloride salt which was isolated as a solid via filtration (0.180g, mass spec. M+1=389).

Example 24 Preparation of6-(2-fluorobenzyl)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0240]

[0241] A mixture of sulfone 8 (0.35 g, 1.01 mmol) and4-amino-tetrahydropyran (Combi-Blocks-vendor, 0.35 g, 3.47 mmol) in 0.3mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3 hours. Thereaction mixture was cooled, poured into water and extracted with ethylacetate (2×, 50 mL). The organic solution was washed with water (5×, 25mL) and dried (brine, MgSO₄). Evaporation of the solvent and columnchromatography (SiO₂, CH₂Cl₂/MeOH—95/5) provided the product which wastransferred to a flask with methanol (5 mL). Dropwise addition ofhydrochloric acid in ether (1M, 1.5 eq) followed by stirring for 1 houryielded the hydrochloride salt which was isolated as a solid viafiltration (0.299 g, mass spec. M+=369, MP=198.4-201.6° C.).

Example 25 Preparation of6-[(4-fluorophenyl)thiol-]-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0242]

[0243] A mixture of sulfide 2 (0.333 g, 1.0 mmol) andtrans-4-aminocyclohexanol (0.345 g, 3.0 mmol) in 0.3 mL of1-methyl-2-pyrrolidinone was heated to 120° C. for 24 hours. Thereaction mixture was cooled, poured into water and stirred for 2 hours.The resultant solid was filtered, rinsed with water (2×) and dried. Theproduct was transferred to a flask with methanol (5 mL) and hydrochloricacid in ether (1M, 1.5 eq) was added dropwise. The organic solvents wereevaporated under reduced pressure and ether/methanol was added. Stirringfor 2 hours followed by filtration and drying yielded the hydrochloridesalt which was isolated as a solid (0.286 g, mass spec. M+1=401,MP=246.2-247.5° C.).

Example 26 Preparation of6-(4-fluorophenoxy)-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0244]

[0245] A mixture of 4-fluorophenoxy sulfide (see Example 8—Step A, 0.4g, 1.26 mmol) and trans-4-aminocyclohexanol (0.7 g, 6.0 mmol) in 0.5 mLof 1-methyl-2-pyrrolidinone was heated to 120° C. for 24 hours. Thereaction mixture was cooled, poured into water and extracted with ethylacetate (2×, 50 mL). The organic solution was washed with water (5×, 25mL) and dried (brine, MgSO₄). Evaporation of the solvent andchromatography (SiO₂, CH₂Cl₂/MeOH—95/5) provided the product which wastransferred to a flask with methanol (5 mL). Dropwise addition ofhydrochloric acid in ether (1M, 1.5 eq) followed by stirring for 1 houryielded the hydrochloride salt which was isolated as a solid viafiltration (0.286 g, mass spec. M+1=385, MP=253.2-253.9° C.).

Example 27 Preparation of6-(2-fluorobenzyl)-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0246]

[0247] A mixture of sulfone 8 (0.348 g, 1.0 mmol) andtrans-4-aminocyclohexanol (0.35 g, 3.0 mmol) in 0.35 mL of1-methyl-2-pyrrolidinone was heated to 80° C. for 30 minutes. Thereaction mixture was cooled and methanol (0.2-0.5 mL) was added withstirring. The product precipitated and was isolated via filtration. Thesolid was transferred to a flask with methanol (5 mL). Dropwise additionof hydrochloric acid in ether (1M, 1.5 eq) followed by stirring for 30minutes yielded the hydrochloride salt which was isolated as a solid(0.233 g, mass spec. M+1=383, MP=229.5-230.2° C.).

Example 28 Preparation of 6-(2-fluorophenoxy)-2-[(4-methoxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one:

[0248]

[0249] Step A: Preparation of6-(2-fluorophenoxy)-2-[(4-hydroxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0250] A mixture of sulfone 2 (0.20 g, 1.15 mmol) andtrans-4-aminocyclohexanol (0.123 g, 1.15 mmol) in 2 mL of1-methyl-2-pyrrolidinone was heated to 120° C. for 17 hours. Thereaction mixture was cooled to room temperature, evaporated underreduced pressure and purified by column chromatography (SiO₂,CH₂Cl₂/MeOH—95/5). Fractions containing product were combined andevaporated to yield 0.20 g of the product. This was taken directly on toStep B.

[0251] Step B: Preparation of6-(2-fluorophenoxy)-2-[(4-methoxycyclohexyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0252] To a slurry of freshly prepared silver oxide (filtered/dried froman aqueous mixture of silver nitrate, 0.44 g, 2.70 mmol) and sodiumhydroxide (0.21 g, 5.20 mmol)) in 2 mL tetrahydrofuran was addedpyrimidin-7(8H)-one (Step A, 0.20 g, 0.52 mmol) and methyl iodide (0.065mL, 1.04 mmol). After stirring at 50° C. for three days, additionalsilver oxide and methyl iodide (0.98 mL, 15.7 mmol) were added; thetemperature was increased to reflux and the reaction continued for 2weeks. Following this time period, the mixture was cooled to roomtemperature, evaporated and purified by column chromatography (SiO₂,CH₂Cl₂/MeOH/NH₄OH—90/9/1). Fractions containing product were combinedand evaporated under reduced pressure to provide the free amine. Thiswas dissolved in methanol (1-2 mL) and hydrochloric acid in ether (1M,1.0 eq) was added. Isolation of the solid via filtration, rinsing withether and drying provided 0.030 g of the hydrochloride salt (Mass spec.M+1=399, MP=135.0-145.0° C.).

Example 29 Preparation of 6-(2-fluorophenoxy)-8-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one:

[0253]

[0254] Step A: Preparation of Benzyl 1-benzylpiperidin-4-ylcarbamate

[0255] To a 0° C. solution of 4-amino-1-benzylpiperidine (41.2 g, 216.5mmol) and triethylamine (51.3 mL, 369 mmol) in 600 mL of tetrahydrofuranwas added benzyl chloroformate (31 mL, 217 mmol) dropwise over a periodof 30 to 45 min. at such a rate that the reaction temperature was keptbetween 5° C. and 10° C. After the addition was complete, the reactionmixture was allowed to warm to room temperature and stir for 12 hours.The solvent and volatiles were removed under reduced pressure. Water(500 mL) and ethyl acetate (1.2 L) were then added and the reaction waspartitioned between the two phases. The organic layer was washed withsaturated aqueous sodium bicarbonate solution (2×, 150 mL) and thendried (brine, MgSO₄). Evaporation of the solvent yielded a tan liquidwhich was purified via column chromatography (SiO₂, EtOAc/Hexane—30/70to EtOAc—100) to provide 27.8 g of the amine as a white solid (massspec. M+=324, MP=79.1-79.6° C.).

[0256] Step B: Preparation of Benzyl Piperidin-4-ylcarbamate

[0257] The benzyl amine (27.8 g, 85.7 mmol) was dissolved in 400 mL ofmethylene chloride at room temperature and 1-chloro-ethylchloroformate(25.4 g, 178 mmol) in 50 mL of methylene chloride was added dropwise viaaddition funnel. After addition was complete, the reaction mixture wasstirred at room temperature for 3 hours. The solvent and volatiles wereremoved under reduced pressure and methanol 500 mL) was added. Thereaction was heated to reflux with stirring for 1 hour and then cooledto room temperature. Removal of the reaction solution via evaporationyielded 26.3 g of the piperidine as an off-white solid (mass spec.M+1=235, MP=190.7-192.2° C.).

[0258] Step C: Preparation of benzyl1-(methylsulfonyl)piperidin-4-ylcarbamate

[0259] The protected piperidine (10 g, 42.7 mmol) and triethylamine (12mL, 86.7 mmol) was dissolved in 500 mL of methylene chloride at roomtemperature. Methane sulfonylchloride (4.3 mL, 55.5 mmol) in 20 mL ofmethylene chloride was added dropwise via addition funnel. Afteraddition was complete, the reaction mixture was stirred at roomtemperature for 3 hours. The solvent and volatiles were removed underreduced pressure. Ethyl acetate (500 mL) and an aqueous solution ofhydrochloric acid (0.5M, 350 mL) was added. The reaction was partitionedbetween the two phases and the aqueous layer was removed. The organiclayer was washed again with an aqueous solution of hydrochloric acid(0.5M, 2×, 100 mL) and then with saturated aqueous sodium bicarbonatesolution (3×, 100 mL). The reaction solvent was then dried (brine,MgSO₄) and evaporated at reduced pressure to provide 9.2 g of themethane sulfonamide (MP=148.6-152.8° C.).

[0260] Step D: Preparation of 1-(methylsulfonyl)piperidin-4-amine

[0261] The methane sulfonamide (9.2 g, 29.5 mmol) was dissolved in 200mL of tetrahydrofuran at room temperature in a 500 mL round-bottomedflask under a nitrogen atmosphere. Palladium on Carbon (10%, 2-3 g) wasthen added and the reaction vessel was flushed with hydrogen gas (3×). Aballoon of hydrogen gas was put on the reaction flask and the solutionwas stirred for 15 hours (more catalyst added and hydrogen balloonfilled if necessary). Methylene chloride (100 mL) was added to thereaction and it was filtered through a celite pad. Evaporation of thesolvents under reduced pressure provided 4.63 g of the desired amine(mass spec. M+1=179, MP=65.3-65.7° C.).

[0262] Step E: Preparation of 6-(2-fluorophenoxy)-8-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0263] A mixture of sulfone 2 (0.2 g, 0.57 mmol) and1-(methylsulfonyl)piperidin-4-amine (Example 29—Steps A-D, 0.243 g, 1.36mmol) in 0.45 mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3hours. The reaction mixture was cooled and methanol (0.2-0.5 mL) wasadded. The product precipitated and was isolated via filtration. Thesolid was transferred to a flask with methanol (5 mL). Dropwise additionof hydrochloric acid in ether (1M, 1.5 eq) followed by stirring yieldedthe hydrochloride salt which was isolated as a solid (0.143 g, massspec.M+1=448).

Example 30 Preparation of6-(2-fluorophenoxy)-8-(4-fluorophenyl)-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0264]

[0265] A mixture of sulfone 11 (0.2 g, 0.46 mmol) and1-(methylsulfonyl)piperidin-4-amine (Example 29—Steps A-D, 0.112 g, 0.62mmol) in 0.2 mL of 1-methyl-2-pyrrolidinone was heated to 110° C. for 1hour. The reaction mixture was cooled and ethyl acetate (40 mL) wasadded. The reaction was transferred, dried (brine, MgSO₄) and evaporatedto provide a crude product. Purification of this via chromatography(SiO₂, prep. TLC plate, EtOAc/Hexane—80/20) followed by isolation andevaporation under reduced pressure yielded the free amine. This productwas dissolved in methylene chloride and hydrochloric acid in ether (1M,0.4 mL) was added followed by stirring. The hydrochloride salt wasisolated as a solid via filtration and drying (0.13 g, mass spec.M+1=528, MP=223.4-225° C.).

Example 31 Preparation of8-cyclopropyl-6-(2-fluorophenoxy)-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0266]

[0267] A mixture of sulfone 10 (0.361 g, 0.97 mmol) and1-(methylsulfonyl)piperidin-4-amine (Example 29—Steps A-D, 0.262 g, 1.47mmol) in 0.4 mL of 1-methyl-2-pyrrolidinone was heated to 110° C. for 2hours. The reaction mixture was cooled and ethyl acetate (40 mL) andwater (40 mL) were added. The reaction mixture was partitioned betweenthe two layers and the aqueous layer was discarded. The organic layerwas then dried (brine, MgSO₄) and evaporated to provide a crude product.Purification of this with chromatography (SiO₂, prep. TLC plate,EtOAc/Hexane—80/20) followed by isolation and evaporation under reducedpressure yielded the free amine. This product was dissolved in methylenechloride and hydrochloric acid in ether (1M, 1.5 eq) was added followedby stirring. The hydrochloride salt was isolated as a solid viafiltration and drying (0.27 g, mass spec. M+1=474).

Example 32 Preparation of6-(2-chlorophenoxy)-8-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0268]

[0269] A mixture of sulfone 6 (0.2 g, 0.55 mmol) and1-(methylsulfonyl)piperidin-4-amine (Example 29—Steps A-D, 0.195 g, 1.09mmol) in 0.2 m L of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3hours. The reaction mixture was cooled and methanol (1 mL) was added.The product precipitated and was isolated via filtration. The solid wastransferred to a flask with methanol (5 mL). Dropwise addition ofhydrochloric acid in ether (1M, 1.5 eq) followed by stirring yielded thehydrochloride salt which was isolated as a solid (0.145 g, mass spec.M+1=465).

Example 33 Preparation of6-(4-chlorophenoxy)-8-methyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0270]

[0271] A mixture of sulfone 7 (0.17 g, 0.46 mmol) and1-(methylsulfonyl)piperidin-4-amine (Example 29—Steps A-D, 0.164 g, 0.92mmol) in 0.2 mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3hours. The reaction mixture was cooled and methanol (1 mL) was added.The product precipitated (3 days) and was isolated via filtration. Thesolid was transferred to a flask with methanol (5 mL). Dropwise additionof hydrochloric acid in ether (1M, 1.5 eq) followed by stirring yieldedthe hydrochloride salt (0.2 g, mass spec. M+1=465).

Example 34 Preparation of2-(cyclopropylamino)-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0272]

[0273] A mixture of sulfone 2 (0.35 g, 1.0 mmol) and cyclopropylamine (1mL, 14 mmole) was heated to 60° C. for 8 hours under a nitrogenatmosphere. The reaction mixture was cooled, evaporated under reducedpressure and purified via column chromatography (SiO₂,Hexane/EtOAc—3/2). The product was suspended in methanol, hydrochloricacid in ether (1M, 1.5 eq) was added and the reaction was stirred for 30minutes. Isolation of the solid via filtration and drying provided thehydrochloride salt (Mass spec. M+1=327, MP=178.2-179.6° C.).

Example 35 Preparation of2-(cyclopentylamino)-6-(4-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0274]

[0275] A mixture of 4-fluorophenoxy sulfone (see Example 8, substitutingmethyl 4-fluorophenoxyacetate for methyl 2-fluorophenoxyacetate-StepA-B, 0.4 g, 1.26 mmol) and cyclopentylamine (Aldrich, 0.146 g, 1.71mmol) in 0.3 mL of 1-methyl-2-pyrrolidinone was heated to 80° C. for 3hours. The reaction mixture was cooled and methanol (1 mL) was added.The product precipitated and was isolated via filtration. The solid wastransferred to a flask with methanol (5 mL). Dropwise addition ofhydrochloric acid in ether (1M, 1.5 eq) followed by stirring yielded thehydrochloride salt (0.165 g, mass spec. M+1=355).

Example 36 Preparation of2-(cyclopentylamino)-6-(3-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0276]

[0277] A mixture of sulfone 3 (0.2 g, 0.57 mmol) and cyclopentylamine(0.146 g, 1.71 mmol) in 0.3 mL of 1-methyl-2-pyrrolidinone was heated to80° C. for 4 hours under a nitrogen atmosphere. The reaction mixture wascooled and methanol (1 mL) was added. The product precipitated and wasisolated via filtration. The solid was transferred to a flask withmethanol (5 mL). Dropwise addition of hydrochloric acid in ether (1M,1.5 eq) followed by stirring yielded the hydrochloride salt (0.105 g,mass spec. M+1=355).

Example 37 Preparation of2-(butylamino)-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0278]

[0279] A mixture of sulfone 2 (0.05 g, 0.143 mmol) and butylamine (0.017g, 0.17 mmol) in 0.2 mL of 1-methyl-2-pyrrolidinone was heated to 65° C.for 12 hours. The reaction mixture was cooled, methanol/water (90/10, 1mL) was added and a precipitate formed. The product was washed withwater, dissolved in methylene chloride and evaporated under reducedpressure to yield the amine (0.019 g, mass spec. M+1=343).

Example 38 Preparation of 6-(2-fluorophenoxy)-2-[(2-hydroxyethyl)amino]-8methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0280]

[0281] A mixture of sulfone 2 (0.05 g, 0.143 mmol), 2-aminoethanol(0.015 g, 0.2 mmol) in 0.2 mL of chloroform was heated to 65° C. for 12hours. The reaction mixture was cooled and the chloroform was removedvia evaporation. Methanol/water (90/10, 1 mL) was added and aprecipitate formed. The product was washed with water, dissolved inmethylene chloride and evaporated under reduced pressure to yield theamine (0.027 g, mass spec. M+1=331).

Example 39 Preparation of6-(2-fluorophenoxy)-2-(isobutylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0282]

[0283] A mixture of sulfone 2 (0.05 g, 0.143 mmol), isobutylamine (0.013g, 0.18 mmol) in 0.2 mL of chloroform was heated to 65° C. for 12 hours.The reaction mixture was cooled and the chloroform was removed viaevaporation. Methanol/water (90/10, 1 mL) was added and a precipitateformed. The product was washed with water, dissolved in methylenechloride and evaporated under reduced pressure to yield the amine (0.038g, mass spec. M+1=343).

Example 40 Preparation of 6-(2-fluorophenoxy)-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0284]

[0285] A mixture of sulfone 2 (0.05 g, 0.143 mmol) and(2S)-2-amino-3-methylbutan-1-ol (0.044 g, 0.43 mmol) in 0.1 mL of1-methyl-2-pyrrolidinone was heated to 80° C. for 3 hours. The reactionmixture was cooled, methanol/water (90/10, 1 mL) was added and aprecipitate formed. The product was washed with water, dissolved inmethylene chloride, filtered through a drying agent (MgSO₄) andevaporated under reduced pressure to yield the amine (0.047 g, massspec. M+1=373).

Example 41 Preparation of2-[(2,3-dihydroxypropyl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0286]

[0287] A mixture of sulfone 2 (0.05 g, 0.143 mmol) and3-aminopropane-1,2-diol (0.016 g, 0.18 mmol) in 0.1 mL of1-methyl-2-pyrrolidinone was heated to 65° C. for 3 hours. The reactionmixture was cooled, methanol/water (90/10, 1 mL) was added but noprecipitate formed. Therefore removed all solvents via evaporation underreduced pressure, added water (1 mL) and ethyl acetate (1 mL) andpartitioned product into the organic layer. The aqueous layer wasremoved; the ethyl acetate was dried (MgSO₄) and evaporated to providethe amine (0.034 g, mass spec. M+1=361).

Example 42 Preparation of6-(2-fluorophenoxy)-8-methyl-2-[(2-piperidin-1-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0288]

[0289] A mixture of sulfone 2 (0.05 g, 0.143 mmol),2-piperidin-1-ylethylamine (0.022 g, 0.17) mmol in 0.2 mL of chloroformwas heated to 65° C. for 12 hours. The reaction mixture was cooled andthe solvents were removed via evaporation. Methanol/water (90/10, 1 mL)was added and a precipitate formed. The product was washed with water,dissolved in methylene chloride and evaporated to yield the amine (0.041g, mass spec. M+1=398).

Example 43 Preparation of2-[(cyclohexylmethyl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0290]

[0291] A mixture of sulfone 2 (0.05 g, 0.143 mmol),cyclohexylmethylamine (0.019 g, 0.17 mmol) in 0.2 mL of chloroform washeated to 65° C. for 12 hours. The reaction mixture was cooled and thesolvents were removed via evaporation. Methanol/water (90/10, 1 mL) wasadded and a precipitate formed. The product was washed with water,dissolved in methylene chloride and evaporated to yield the amine (0.045g, mass spec. M+1=383).

Example 44 Preparation of 2-[(cyclopropylmethyl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0292]

[0293] A mixture of sulfone 2 (0.05 g, 0.143 mmol),cyclopropylmethylamine (0.02 g, 0.28 mmol) in 0.2 mL of chloroform washeated to 65° C. for 12 hours. The reaction mixture was cooled and thesolvents were removed via evaporation. Methanol/water (90/10, 1 mL) wasadded and a precipitate formed. The product was washed with water,dissolved in methylene chloride and evaporated under reduced pressure toyield the amine (0.03 g, mass spec. M+1=341).

Example 45 Preparation of6-(2-fluorophenoxy)-2-[(2-methoxyethyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0294]

[0295] A mixture of sulfone 2 (0.05 g, 0.143 mmol), 2-methoxyethylamine(0.02 g, 0.27 mmol) in 0.2 mL of chloroform was heated to 65° C. for 12hours. The reaction mixture was cooled and the solvents were removed viaevaporation. Methanol/water (90/10, 1 mL) was added and a precipitateformed. The product was washed with water, dissolved in methylenechloride and evaporated under reduced pressure to yield the amine (0.04g, mass spec. M+1 345).

Example 46 Preparation of2-{[3-(dimethylamino)propyl]amino}-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H1)-one

[0296]

[0297] A mixture of sulfone 2 (0.05 g, 0.143 mmol),N,N-dimethylpropane-1,3-diamine (0.018 g, 0.18 mmol) in 0.2 mL ofchloroform was heated to 65° C. for 12 hours. The reaction mixture wascooled and the solvents were removed via evaporation. Methanol/water(90/10, 1 mL) was added and a precipitate formed. The product was washedwith water, dissolved in methylene chloride and evaporated to yield theamine (0.045 g, mass spec. M+1=372).

Example 47 Preparation of6-(2-fluorophenoxy)-8-methyl-2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0298]

[0299] A mixture of sulfone 2 (0.05 g, 0.143 mmol),1-(3-aminopropyl)pyrrolidin-2-one (0.024 g, 0.17 mmol) in 0.2 mL ofchloroform was heated to 65° C. for 12 hours. The reaction mixture wascooled and the solvents were removed via evaporation. Methanol/water(90/10, 1 mL) was added and a precipitate formed. The product was washedwith water, dissolved in methylene chloride and evaporated to yield theamine (0.033 g, mass spec. M+1=412).

Example 48 Preparation ofN-(2-{[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)acetamide

[0300]

[0301] A mixture of sulfone 2 (0.05 g, 0.143 mmol),N-(2-aminoethyl)acetamide (0.024 g, 0.18 mmol) in 0.2 mL of chloroformwas heated to 65° C. for 12 hours. The reaction mixture was cooled andthe solvents were removed via evaporation. Methanol/water (90/10, 1 mL)was added and a precipitate formed. The product was washed with water,dissolved in methylene chloride and evaporated to yield the amine (0.035g, mass spec. M+1=373).

Example 49 Preparation of6-(2-fluorophenoxy)-8-methyl-2-[(2-pyridin-3-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0302]

[0303] A mixture of sulfone 2 (0.05 g, 0.143 mmol),2-pyridin-3-ylethylamine (0.021 g, 0.17 mmol) in 0.2 mL of chloroformwas heated to 65° C. for 12 hours. The reaction mixture was cooled andthe solvents were removed via evaporation. Methanol/water (90/10, 1 mL)was added and a precipitate formed. The product was washed with water,dissolved in methylene chloride and evaporated to yield the amine (0.039g, mass spec. M+1=392).

Example 50 Preparation of ethylN-[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]-β-alaninate

[0304]

[0305] To a solution of ethyl β-alaninate hydrochloride salt (0.053 g,0.34 mmol) in 3 mL of chloroform at room temperature was added MPCarbonate Resin (Argonaut Technologies Inc., 0.45 g). This was allowedto stir for 1 hour and then Sulfone 2 (0.05 g, 0.143 mmol) was added.The reaction was brought to 65° C. and stirred for 24 hours. The mixturewas then cooled and the resin was removed via filtration. Evaporation ofthe solvent and chromatography (SiO₂, CH₂Cl₂/MeOH—95/5) and subsequentevaporation of appropriate fractions provided the amine (0.027 g, massspec. M+1=387).

Example 51 Preparation of6-(2-fluorophenoxy)-2-[(3-methoxypropyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0306]

[0307] A mixture of sulfone 2 (0.05 g, 0.143 mmol), 3-methoxypropylamine(0.015 g, 0.17 mmol) in 1.5 mL of chloroform was heated to 65° C. for 12hours. The reaction mixture was cooled and the solvents were removed viaevaporation. The crude reaction mixture was purified via columnchromatography (Supelco 3 mL plug, SiO₂, CH₂Cl₂/MeOH—95/5) andsubsequent evaporation to provide the amine (0.027 g, mass spec.M+1=359).

Example 52 Preparation of6-(4-chlorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one:

[0308]

[0309] Step A: Preparation of Tert-Butyl (1S)-2-hydroxy-1,2-dimethylPropyl Carbamate

[0310] To a 0° C. solution of methyl N-(tert-butoxycarbonyl)-L-alaninate(10.0 g, 49.3 mmol) in 70 mL of tetrahydrofuran under a nitrogenatmosphere was added methylmagnesium chloride (3.0M in THF, 70 mL, 210mmol) dropwise over a period of 30 to 45 min. After the addition wascompleted, the reaction mixture was allowed to warm to room temperatureand stir for 2 hours. The solvent and volatiles were removed underreduced pressure. Water (500 mL) and ethyl acetate (1.2 L) were thenadded and the reaction was partitioned between the two phases. Theorganic layer was dried (brine, MgSO₄) and evaporation of the solventyielded a liquid which was chromatographed (SiO₂, CH₂Cl₂/MeOH—90/10)providing 9.6 g of the protected amine as a liquid (mass spec. M+1=204).

[0311] Step B: Preparation of (3S)-3-amino-2-methylbutan-2-ol

[0312] To a 0° C. solution of the carbamate (9.6 g, 47.3 mmol) in 96 mLof methylene chloride under a nitrogen atmosphere was addedtrifluoroacetic acid (4 mL, 51.9 mmol) dropwise. After the addition wascompleted, the reaction mixture was allowed to warm to room temperatureand stir for 2 hours. t-Butanol (2-3 mL) was added to the reaction andthe solvent/volatiles were removed under reduced pressure. Addition oftoluene (3×, 75 mL) with evaporation followed by drying in a vacuum ovenprovided the crude amine which was a solid. This material wastransferred to a flask and methanol (10 mL) and hydrochloric acid (12M,5-7 mL) were then added with stirring. After 30 minutes, thehydrochloride salt of the amine formed as a precipitate and this wasrinsed with toluene (50 mL) and Et₂O (2×, 150 mL) and then dried underreduced pressure (mass spec. M+1=104, MP=128.1-130.1° C.). Note: Thisamine is hydroscopic and care was taken to not allow extensive exposureto air/water during isolation.

[0313] Step C: Preparation of6-(4-chlorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0314] To a solution of (3S)-3-amino-2-methylbutan-2-ol hydrochloridesalt (0.077 g, 0.55 mmol) in 3 mL of chloroform at room temperature wasadded MP Carbonate Resin (Argonaut Technologies Inc., Foster City,Calif., 0.75 g). This was allowed to stir for 1 hour and then Sulfone 7(0.1 g, 0.28 mmol) was added. The reaction was brought to 60° C. andstirred for 24 hours. The mixture was then cooled and the resin wasremoved via filtration. Evaporation of the solvent and columnchromatography (SiO₂, CH₂Cl₂) provided a crude product which waschromatographed a second time (SiO₂, CH₂Cl₂/Hexane—1/1 gradient toCH₂Cl₂/MeOH—99/1). Isolation of the appropriate fractions followed bysolvent evaporation at reduced pressure yielded the amine (0.032 g, massspec. M+1=389).

Example 53 Preparation of6-(2,4-difluorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0315]

[0316] To a solution of (3S)-3-amino-2-methylbutan-2-ol hydrochloridesalt (0.24 g, 1.77 mmol) in 3 mL of acetonitrile at room temperature wasadded trimethylsilyl cyanide (Aldrich, 0.7 mL, 5.2 mmol). This wasrefluxed for 30 minutes, cooled to room temperature and then Sulfone 5(0.367 g, 1.0 mmol) was added. The reaction was refluxed for 2 hours andcooled to room temperature. Methanol (2 mL) and aqueous sodium hydroxidesolution (2N, 1-3 mL) was added and the mixture was refluxed for 30minutes. The reaction was evaporated and ethyl acetate (25 mL) wasadded. Drying of the organic solution (brine, 3×), followed byevaporation under reduced pressure and chromatography (SiO₂, prep. TLCplate, EtOAc/Hexane—75/25) provided the crude product. This wasdissolved in methylene chloride (1-2 mL) and hydrochloric acid in ether(1M, X's) was added. Isolation of the solid via filtration and dryingprovided 0.16 g of the hydrochloride salt (Mass spec. M+1=391,MP=104.3-107.5° C.).

Example 54 Preparation of6-(2-fluorobenzyl)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8TH-one

[0317]

[0318] To a solution of (3S)-3-amino-2-methylbutan-2-ol hydrochloridesalt (0.31 g, 2.21 mmol) in 3 mL of acetonitrile at room temperature wasadded N,N-diisopropylethylamine (0.7 mL, 4 mmol). This was refluxed for30 minutes, cooled to room temperature and then Sulfone 8 (0.4 g, 1.15mmol) was added. The reaction was refluxed for 2 hours and cooled toroom temperature. Ethyl acetate (25 mL) was added and this solution wasdryed (brine ×3×, MgSO₄). Evaporation under reduced pressure andchromatography (SiO₂, prep. TLC plate, EtOAc/Hexane—75/25) provided thecrude product. This was dissolved in methylene chloride (1-2 mL) andhydrochloric acid in ether (1M, X's) was added. Isolation of the solidvia filtration and drying provided 0.25 g of the hydrochloride salt(Mass spec. M+1=371, MP=162.9-170.5° C.).

Example 55 Preparationof6-(2-fluorophenoxy)-8-methyl-2-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:

[0319]

[0320] Step A: Preparation tetrahydro-4H-thiopyran-4-one Oxime:

[0321] A suspension mixture of tetrahydrothiopyran-4-one (5 g, 43 mmol),sodium acetate trihydrate (29.26 g, 215 mmol) and hydroxylaminehydrochloride (14.9 g, 215 mmol) in 200 mL of ethanol were heated toreflux for 6 hours. The reaction mixture was cooled andsolvent/volatiles were removed under reduced pressure. The residue wasdiluted with ice water (400 mL) and extracted with ethyl acetate (3×,150 mL). The organic solution was dried (brine, MgSO₄) and evaporatedaffording 5.6 g of the thianone oxime as a white solid (mass spec.M+=131).

[0322] Step B: Preparation 4-aminotetrahydrothiopyran:

[0323] To a solution of lithium aluminum hydride (1M, 76 mL, 76 mmol) intetrahydrofuran at room temperature under a nitrogen atmosphere (1M, 76mL, 76 mmole) was added dropwise the thianone oxime (2 g, 15 mmol) in 30mL of tetrahydrofuran. After addition was completed, the mixture wasstirred at reflux for 7 hours and then room temperature for 12 hours.Water (2.9 mL) was added slowly (dropwise) to the suspension, followedby an aqueous solution of sodium hydroxide (15%, 2.9 mL). Additionalwater (8.7 mL) was then added and the reaction mixture was stirred for30 minutes, filtered through a celite pad and rinsed with ethyl acetate(200 mL). The filtrate was dried (brine, MgSO₄) and evaporated underreduced pressure affording 1.62 g of the 4-aminotetrahydrothiopyran(mass spec. M+1=118).

[0324] Step C. Preparation6-(2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-thiopyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0325] A mixture of sulfone 2 (1.0 g, 2.9 mmol) and4-aminotetrahydrothiopyran (0.67 g, 5.8 mmol) in 1 mL of1-methyl-2-pyrrolidinone was heated at 80° C. for 1 hour. The reactionmixture was cooled, ethyl acetate (100 mL) was added and the organicsolution was washed with water (3×, 75 mL) and then dried (brine,MgSO₄). Evaporation of the solvent under reduced pressure and columnchromatography (SiO₂, EtOAc/Hexane—40/60) afforded 0.84 g of the sulfideas a white solid which was taken on to Step D.

[0326] Step D: Preparation6-(2-fluorophenoxy)-8-methyl-2-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:

[0327] The sulfide (0.84 g, 2.2 mmol) was dissolved in 80 mL ofdichloromethane and was cooled to 5° C. as 3-chloroperbenzoic acid (77%,0.5 g, 2.2 mmol) was added in three portions over a period of 30minutes. Reaction was completed in 30 minutes and the mixture was washedwith aqueous sodium sulfite solution (10%, 100 mL) followed by coldsaturated aqueous sodium bicarbonate solution. The solution was dried(brine, Na₂SO₄) and evaporated under reduced pressure. The product waspurified by column chromatography (SiO₂, CH₂Cl₂/MeOH—95/5) yielding theamine sulfoxide. This product (0.4 g) was dissolved in ethylacetate/dichloromethane (1/1, 1 mL) and hydrochloric acid in ether (1M,1.2 mL 1.2 eq) was added. A white suspension formed and this was stirredfor 15 minutes. Filtration of the solid and rinsing with ether yielded385 mg of the hydrochloride salt (mass spec. M+1=403, MP=188.8-189.7°C.).

Example 56 Preparation of2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0328]

[0329] A mixture of the sulfoxide (0.47 g, 1.2 mmol) and3-chloroperbenzoic acid (0.26 g, 1.2 mmol) in 50 mL of dichloromethanewas stirred at room temperature for 2 hours under a nitrogen atmosphere.The reaction was then quenched with an aqueous sodium sulfite solution(10%, 100 mL), then washed with cold saturated aqueous sodiumbicarbonate solution (100 mL). The organic solution was dried (brine,Na₂SO₄), evaporated under reduced pressure, and purified via columnchromatography (SiO₂, CH₂Cl₂/MeOH—97/3) affording 0.45 g of the sulfone.This was dissolved in methanol/dichioromethane (5/95, 1 mL) andhydrochloric acid in ether (1M, 1.3 mL) was added. A suspension formedand this was stirred for 30 minutes. Filtration of the solid and rinsingwith ether yielded 413 mg of the hydrochloride salt (mass spec. M+1=419,MP=186.2-230.7° C., sample partially melted throughout the range).

Example 57 Preparation of 6-(2,4-difluorophenoxy)-8-methyl-2-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:

[0330]

[0331] Step A: Preparation6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-thiopyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0332] A mixture of sulfone 5 (1.14 g, 3.1 mmol) and4-aminotetrahydrothiopyran (0.73 g, 6.2 mmol) in 2 mL of1-methyl-2-pyrrolidinone was heated at 70° C. for 15 minutes. Thereaction mixture was cooled, ethyl acetate (100 mL) was added. Theorganic solution was then washed with water (3×, 75 mL) and dried(brine, MgSO₄). Evaporation of the solvent and column chromatography(SiO₂, CH₂Cl₂/EtOAc—90/10) afforded 0.9 g of the sulfide (mpt.230.7-232.8, MS (M+H)=405) which was taken on to Step B.

[0333] Step B: Preparation 6-(2,4-difluorophenoxy)-8-methyl-2-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one:

[0334] The sulfide (0.9 g, 2.2 mmol) was dissolved in 80 mL ofdichloromethane and was cooled to 5° C. as 3-chloroperbenzoic acid (77%,0.5 g, 2.2 mmol) was added in three portions over a period of 30minutes. Reaction was completed in 20 minutes and the mixture wasquenched with aqueous sodium sulfite solution (10%, 100 mL) followed bycold saturated aqueous sodium bicarbonate solution. The solution wasdried (brine, MgSO₄) and evaporated under reduced pressure. The productwas purified by column chromatography (SiO₂, CH₂Cl₂/MeOH—95/5) yieldingthe amine sulfoxide. This product (0.35 g, 0.8 mmol) was dissolved in 1ml of dichloromethane and hydrochloric acid in ether (1M, 1.0 mL) wasadded. A suspension formed and this was stirred for 15 minutes. Dilutionof the solid with ether (10 mL), filtration and rinsing with etheryielded 344 mg of the hydrochloride salt (mass spec. M+1 421,MP=201.8-202.5° C.).

Example 58 Preparation of2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-6-(2,4-difluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0335]

[0336] A mixture of the sulfoxide (0.6 g, 1.4 mmol) and3-chloroperbenzoic acid (0.48 g, 1.5 mmol) in 50 mL of dichloromethanewas stirred at room temperature for 12 hours under a nitrogenatmosphere. The reaction was then quenched with an aqueous sodiumsulfite solution (10%, 100 mL), then washed with cold saturated aqueoussodium bicarbonate solution (100 mL). The organic solution was dried(brine, Na₂SO₄), evaporated under reduced pressure, and purified viacolumn chromatography (SiO₂, CH₂Cl₂/MeOH—95/5) affording 0.41 g of thesulfone. This was dissolved in methanol/dichloromethane (5/95, 1 mL),hydrochloric acid in ether (1M, 1.1 mL) was added and the solution wasstirred for 15 minutes. Evaporation under reduced pressure followed byaddition of ether (10 mL) and stirring provided a solid. Filtration ofthe precipitate and rinsing with ether yielded 382 mg of thehydrochloride salt (mass spec. M+1=437, MP=251.7-254.9° C.).

Example 59 Preparation of 6-(2,6-difluorophenoxy)-2-{[1-(hydroxymethyl)butyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8TH-one

[0337]

[0338] A mixture of sulfone 4 (0.38 g, 1 mmol) and 2-aminopentan-1-ol(0.35 g, 3.4 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 80°C. for 1 hour and then cooled to room temperature. Methanol/water (9/1,1-2 mL) was added and the suspension was stirred for 30 minutes.Filtration and washing of the precipitate thoroughly with ether thenwater followed by drying provided the free amine. This was dissolved inmethanol (1-2 mL), hydrochloric acid in ether (1M, X's) was added andthe reaction was stirred for 30 minutes. Evaporation of the organics,followed by addition of ether/methanol (1-2 mL) yielded a precipitate.Isolation of this solid via filtration and drying provided 0.28 g of thehydrochloride salt (Mass spec. M+1=391, MP=176.7-177.7° C.).

Example 60 Preparation of6-(2,6-difluorophenoxy)-2-[(2-hydroxy-1,1-dimethylethyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0339]

[0340] A mixture of sulfone 4 (0.38 g, 1 mmol) and2-amino-2-methylpropan-1-ol (0.35 g, 3.4 mmol) in 0.4 mL1-methyl-2-pyrrolidinone was stirred at 80° C. for 1 hour and thencooled to room temperature. Methanol/water (9/1, 1-2 mL) was added andthe suspension was stirred for 30 minutes. Filtration and washing of theprecipitate thoroughly with ether then water followed by drying providedthe free amine. This was dissolved in methanol (1-2 mL), hydrochloricacid in ether (1 M) was added and the reaction was stirred for 30minutes. Evaporation of the organics, followed by addition ofether/methanol (1-2 mL) yielded a precipitate. Isolation of this solidvia filtration and drying provided 0.212 g of the hydrochloride salt(Mass spec. M+1=377, MP=212.8-213.5° C.).

Example 61 Preparation of 6-(2-fluorophenoxy)-2-{[1-(hydroxymethyl)cyclopentyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0341]

[0342] A mixture of sulfone 2 (0.353 g, 1 mmol),(1-aminocyclopentyl)methanol (0.154 g, 1.42 mmol) in 0.4 mL of1-methyl-2-pyrrolidinone was heated to 80° C. for 1 hour. The reactionmixture was cooled, water (50 mL) and ethyl acetate (50 mL) were thenadded and the reaction was partitioned between the two phases. Theorganic layer was dried (brine, MgSO₄) and evaporation of the solventyielded a residue which was purified via column chromatography (SiO₂,CH₂Cl₂/MeOH—90/10). The column fractions were combined and concentratedunder reduced pressure to provide the free amine. This was suspended inmethanol (1-2 mL), hydrochloric acid in ether (1M, X's) was added andthe reaction was stirred for 30 minutes. Evaporation of the organics,followed by addition of ether/methanol (1-2 mL) yielded a precipitate.Isolation of this solid via filtration and drying provided 0.279 g ofthe hydrochloride salt (Mass spec. M+1=385, MP=198.6-200.3° C.).

Example 62 Preparation of6-(2-fluorophenoxy)-2-{[1-(hydroxymethyl)-3-(methylthio)propyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0343]

[0344] A mixture of sulfone 2 (1.04 g, 2.94 mmol),2-amino-4-(methylthio)butan-1-ol (1.0 g, 9.7 mmol) in 1.0 mL of1-methyl-2-pyrrolidinone was heated to 80° C. for 1 hour. The reactionmixture was cooled and methanol/water (9/1, 5-7 mL) was added but noprecipitate formed. Therefore all solvents were removed via evaporationunder reduced pressure, water (25 mL) and ethyl acetate (25 mL) wereadded. The reaction mixture was partitioned between the two layers andthe aqueous layer was removed. The ethyl acetate solution was dried(brine, MgSO₄) and evaporated under reduced pressure. The crude reactionmixture was purified via column chromatography (SiO₂, CH₂Cl₂/MeOH—95/5)and the column fractions were combined and concentrated under reducedpressure to provide 0.8 g of the free amine. This product (0.2 g) wassuspended in methanol (1-3 mL), hydrochloric acid in ether (1M, X's) wasadded and the reaction was stirred for 30 minutes. Evaporation of theorganics, followed by addition of ether/methanol (1-2 mL) yielded aprecipitate. Isolation of this solid via filtration and drying provided0.125 g of the hydrochloride salt (Mass spec. M+1=405, MP=130.6-132.2°C.).

Example 63 Preparation of2-(benzylamino)-6-(4-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0345]

[0346] A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 made by replacing methyl2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate—Steps A and B,0.35 g, 1.0 mmol) and benzylamine (0.33 mL, 3 mmol) in 0.5 mL of1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and thencooled to room temperature. Methanol (2 mL) was added and the suspensionwas stirred for 30 minutes. Filtration and washing of the precipitatethoroughly with methanol followed by drying provided the free amine.This was dissolved in ethyl acetate (1-2 mL) and hydrochloric acid inether (1M, 1.5 eq) was added. Isolation of the solid via filtration anddrying provided 0.317 g of the hydrochloride salt (Mass spec. M+1=377,MP=203.2-204° C.).

Example 64 Preparation of2-(benzylamino)-6-(4-fluorobenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0347]

[0348] A mixture of sulfone 9 (0.36 g, 1.03 mmol) and benzylamine (0.35mL, 3 mmol) in 0.3 mL of 1-methyl-2-pyrrolidinone was stirred at 80° C.for 1 hour and then cooled to room temperature. Ether (2 mL) was addedand the suspension was stirred for 30 minutes. Filtration and washing ofthe precipitate thoroughly with ether followed by drying provided thefree amine. This was dissolved in methanol (1-2 mL) and hydrochloricacid in ether (1M, X's) was added. Evaporation under reduced pressure,followed by stirring with ether/methanol (1-3 mL) yielded a precipitate.Isolation of the this solid via filtration and drying provided 0.193 gof the hydrochloride salt (Mass spec. M+1=375).

Example 65 Preparation of 6-(2-fluorophenoxy)-8-methyl-2-[(1-phenylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0349]

[0350] A mixture of sulfone 2 (0.1 g, 0.286 mmol), α-ethylbenzylamine(0.088 mL, 0.573 mmole) in 2 mL of 1-methyl-2-pyrrolidinone was heatedto 120° C. for 12 hours. The reaction mixture was cooled and purified bycolumn chromatography (SiO₂, Hexane/Acetone—80/20). The column fractionswere combined and concentrated under reduced pressure to provide thefree amine. This product was taken up in methanol (1-3 mL), hydrochloricacid in ether (1M, 1 eq) was added and the reaction was stirred for 30minutes. Isolation of this solid via filtration, rinsing with ether anddrying provided 0.084 g of the hydrochloride salt (Mass spec. M+1=405,MP=109.4-111.3° C.).

Example 66 Preparation of6-(2-fluorophenoxy)-8-methyl-2-[(pyridin-2-ylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0351]

[0352] A mixture of sulfone 2 (0.05 g, 0.143 mmol),pyridin-2-ylmethylamine (0.154 g, 1.42 mmol) in 0.2 mL of chloroform washeated to 65° C. for 12 hours. The reaction mixture was cooled and thesolvents were removed via evaporation. Methanol/water (90/10, 1 mL) wasadded and a precipitate formed. The product was washed with water,dissolved in methylene chloride and evaporated to yield the amine (0.035g, mass spec. M+1=378).

Example 67 Preparation of 6-(2-fluorophenoxy)-2-[(3-furylmethyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0353]

[0354] A mixture of sulfone 2 (0.05 g, 0.143 mmol), 3-furylmethylamine(0.023 g, 0.23 mmol) in 0.2 mL of chloroform was heated to 65° C. for 12hours. The reaction mixture was cooled and the solvents were removed viaevaporation. Methanol/water (90/10, 1 mL) was added and a precipitateformed. The product was washed with water, dissolved in methylenechloride and evaporated to yield the amine (0.042 g, mass spec.M+1=367).

Example 68 Preparation of 8-methyl-6-phenoxy-2-[(2-phenylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0355]

[0356] A mixture of sulfone 1 (0.33 g, 1 mmol) and phenethylamine (0.380mL, 3 mmol) in 0.5 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C.for 12 hours and then cooled to room temperature. Methanol (2 mL) wasadded and the suspension was stiffed for 30 minutes. Filtration andwashing of the precipitate thoroughly with methanol followed by dryingprovided the free amine. This was suspended in methanol (1-2 mL) andhydrochloric acid in ether (1M, 2 mL) was added. Isolation of the solidvia filtration and drying provided 0.127 g of the hydrochloride salt(Mass spec. M+1=373, MP=211.8-213° C.).

Example 69 Preparation of 6-(2-chlorophenoxy)-8-methyl-2-[(2-phenylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0357]

[0358] A mixture of sulfone 6 (0.365 g, 1 mmol) and phenethylamine (0.4mL, 3.3 mmol) in 0.4 mL of 1-methyl-2-pyrrolidinone was stirred at 80°C. for 1 hour and then cooled to room temperature. Ether (2-3 mL) wasadded but no precipitate formed. Therefore the solvents were removed viaevaporation under reduced pressure, water (5 mL) and ethyl acetate (5mL) were added. The reaction was partitioned between the two layers andthe aqueous layer was removed. The ethyl acetate solution was dried(brine, MgSO₄) and evaporated to provide a residue. Ether (2-3 mL wasadded to this and a precipitate formed. Filtration, rinsing withadditional ether and drying provided the free amine. This solid wassuspended in methanol (1-3 mL), hydrochloric acid in ether (1M, X's) wasadded and the reaction was stirred for 30 minutes. Filtration, washingwith ether and drying provided 0.321 g of the hydrochloride salt (Massspec. M+1=407, MP=210-211° C.).

Example 70 Preparation of Ethyl4-{[6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate

[0359]

[0360] A mixture of sulfone 5 (1.0 g, 2.72 mmol) and ethyl4-amino-1-piperidinecarboxylate (0.93 mL, 5.44 mmol) in 5 mL of1-methyl-2-pyrrolidinone was stirred at 80° C. for 17 hours and thencooled to room temperature. Water (200 mL) was added and the suspensionwas stirred overnight. Filtration and washing of the precipitatethoroughly with methanol followed by drying provided the free amine. Aportion of this product (0.100 g, 0.216 mmol) was dissolved in methanol(1-2 mL) and hydrochloric acid in ether (1M, 1 eq) was added. Isolationof the solid via filtration, followed by rinsing with ether and dryingprovided 0.317 g of the hydrochloride salt (Mass spec. M+1 462,MP=197.0-204.0° C.).

Example 71 Preparation of8-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}-6-phenoxypyrido[2,3-d]pyrimidin-7(8H)-one

[0361]

[0362] A mixture of sulfone 1 (0.33 g, 1 mmol) and1-(3-aminopropyl)-4-methylpiperazine (0.51 mL, 3 mmol) in 0.5 mL1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and thencooled to room temperature. Methanol (2 mL) was added and the suspensionwas stirred for 30 minutes. Filtration and washing of the precipitatethoroughly with methanol followed by drying provided the free amine.This was suspended in methanol (1-2 mL) and hydrochloric acid in ether(1M, 2 mL) was added. Isolation of the solid via filtration and dryingprovided 0.183 g of the hydrochloride salt (Mass spec. M+1=409,MP=180.2-182.2° C.).

Example 72 Preparation of6-(2-chlorophenoxy)-8-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0363]

[0364] A mixture of sulfone 6 (0.38 g, 1 mmol) and1-(3-aminopropyl)-4-methylpiperazine (0.46 mL, 2.9 mmol) in 0.4 mL1-methyl-2-pyrrolidinone was stirred at 80° C. for 1 hour and thencooled to room temperature. Ether (2 mL) was added and the suspensionwas stirred for 2 hours. Filtration and washing of the precipitatethoroughly with ether followed by drying provided the free amine. Thiswas suspended in methanol (1-2 mL), hydrochloric acid in ether (1M, X's)was added and the reaction was stirred for 30 minutes. Evaporation ofthe organics, followed by addition of ether/methanol (1-2 mL) yielded aprecipitate. Isolation of this solid via filtration and drying provided0.44 g of the hydrochloride salt (Mass spec. M+1=443, MP=233.9-235.5°C.).

Example 73 Preparation of2-anilino-6-(4-fluorobenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0365]

[0366] A mixture of sulfone 9 (0.4 g, 1.15 mmol) and aniline (0.4 mL,4.3 mmol) in 0.4 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for12 hours and then cooled to room temperature. Methanol (2 mL) was addedand the suspension was stirred for 30 minutes. Filtration and washing ofthe precipitate thoroughly with methanol followed by drying provided thefree amine. This was suspended in methanol (1-2 mL), hydrochloric acidin ether (1M, X's) was added and the reaction was stirred for 30minutes. Isolation of the solid via filtration, rinsing with ether anddrying provided 0.167 g of the hydrochloride salt (Mass spec. M+1=361,MP=243.1-246.3° C.).

Example 74 Preparation of 6-(4-fluorophenoxy)-2-[(4-fluorophenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0367]

[0368] A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 replacing methyl2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate—Step A-B, 0.35g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and thencooled to room temperature. Methanol (2 mL) was added and the suspensionwas stirred for 30 minutes. Filtration and washing of the precipitatethoroughly with methanol followed by drying provided the crude productwhich was purified by column chromatography (SiO₂, CH₂Cl₂/MeOH—95/5).The column fractions were combined and concentrated under reducedpressure to provide the free amine. This was suspended in ethyl acetate(1-2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added.Isolation of the solid via filtration and drying provided 0.101 g of thehydrochloride salt (Mass spec. M+1=381, MP=242.3-242.6° C.).

Example 75 Preparation of 6-(2,6-dichlorophenoxy)-2-[(4-fluorophenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0369]

[0370] A mixture of6-(2,6-dichlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(see Example 12—Step A-B, (replacing methyl 2-fluorophenoxyacetate withmethyl 2,6-dichlorophenoxyacetate) 0.35 g, 1 mmol) and 4-fluoroaniline(0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at110° C. for 12 hours and then cooled to room temperature. Methanol (2mL) was added and the suspension was stirred for 30 minutes. Filtrationand washing of the precipitate thoroughly with methanol followed bydrying provided the crude product which was purified by columnchromatography (SiO₂, CH₂Cl₂/MeOH—95/5). The column fractions werecombined and concentrated under reduced pressure to provide the freeamine. This was suspended in ethyl acetate (1-2 mL) and hydrochloricacid in ether (1M, 1.2 eq) was added. Isolation of the solid viafiltration and drying provided 0.131 g of the hydrochloride salt (Massspec. M+1=430, MP=248.2-249.1° C.).

Example 76 Preparation of6-(4-fluorobenzyl)-2-[(4-fluorophenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0371]

[0372] A mixture of sulfone 9 (0.36 g, 1 mmol) and 4-fluoroaniline (0.8mL, 7.2 mmol) in 0.4 mL 1-methyl-2-pyrrolidinone was stirred at 110° C.for 12 hours and then cooled to room temperature. Methanol (2 mL) wasadded and the suspension was stirred for 30 minutes. Filtration andwashing of the precipitate thoroughly with methanol followed by dryingprovided the crude product. This was suspended in methanol (1-2 ML),hydrochloric acid in ether (1M, X's) was added and the reaction wasstirred for 1 hour. Isolation of the solid via filtration, rinsing withether and drying provided 0.207 g of the hydrochloride salt (Mass spec.M+1=379, MP=246-250° C.).

Example 77 Preparation of2-{[4-(2-hydroxyethyl)phenyl]amino}-8-methyl-6-phenoxypyrido[2,3-d]pyrimidin-7(8H)-one

[0373]

[0374] A mixture of sulfone 1 (0.331 g, 1 mmol) and2-(4-aminophenyl)ethanol (0.411 g, 3 mmol) in 0.5 mL1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and thencooled to room temperature. Methanol (2 mL) was added and the suspensionwas stirred for 30 minutes. Filtration and washing of the precipitatethoroughly with methanol followed by drying provided the free amine.This was suspended in methanol (1-2 mL), hydrochloric acid in ether (1M,1.5 mL) was added and the reaction was stirred for 30 minutes. Isolationof the solid via filtration and drying provided 0.127 g of thehydrochloride salt (Mass spec. M+1=389).

Example 78 Preparation of 6-(2-chlorophenoxy)-2-({4-[2-(diethylamino)ethoxy]phenyl}amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0375]

[0376] A mixture of sulfone 6 (0.4 g, 1.1 mmol) and4-(2-diethylaniinoethoxy) aniline (0.8 g, 3.8 mmol) in 0.5 mL1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and thencooled to room temperature. Methanol/water (9/1, 1-2 mL) was added andthe suspension was stirred for 30 minutes. Filtration and washing of theprecipitate thoroughly with water followed by drying provided the crudeproduct which was purified by column chromatography (SiO₂,CH₂Cl₂/MeOH—95/5). The column fractions were combined and concentratedunder reduced pressure to provide the free amine. This was suspended inmethanol (1-2 mL), hydrochloric acid in ether (1M, X's) was added andthe reaction was stirred for 30 minutes. Evaporation of the organics,followed by addition of ether/methanol (1-2 mL) yielded a precipitate.Isolation of this solid via filtration and drying provided 0.16 g of thehydrochloride salt (Mass spec. M+=1494, MP=255.5-261.4° C.).

Example 79 Preparation of2-({4-[2-(diethylamino)ethoxy]phenyl}amino)-6-(4-vifluorophenoxy)-8-methylpylido[2,3-d]pyrimidin-7(8H)-one

[0377]

[0378] A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8—Step A-B. 0.35 g, 1mmol) and 4-(2-diethylaminoethoxy) aniline (0.625 g, 3 mmol) in 0.5 mL1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and thencooled to room temperature. Methanol (2 mL) was added and the suspensionwas stirred for 30 minutes. Filtration and washing of the precipitatethoroughly with methanol followed by drying provided the free amine.This was suspended in ethyl acetate (1-2 mL), hydrochloric acid in ether(1M, 1.2 eq) was added and the reaction was stirred for 30 minutes.Isolation of the solid via filtration and drying provided 0.085 g of thehydrochloride salt (Mass spec. M+1=478, MP=245.2-246.1° C.).

Example 80 Preparation of6-(2-fluorophenoxy)-2-[(3-hydroxypyridin-2-yl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0379]

[0380] A mixture of sulfone 2 (0.05 g, 0.143 mmol), 2-aminopyridin-3-ol(0.047 g, 0.43 mmol) in 0.1 mL of 1-methyl-2-pyrrolidinone was heated to80° C. for 3 hours. The reaction mixture was cooled, methanol/water(90/10, 1 mL) was added and a precipitate formed. The product was washedwith water, dissolved in methylene chloride, filtered through a dryingagent (MgSO₄) and evaporated to yield the amine (0.040 g, mass spec.M+1=380).

Example 81 Preparation of6-(2-fluorophenoxy)-8-methyl-2-[(5-methylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one

[0381]

[0382] To a solution of 5-methylpyridin-2-amine hydrochloride salt(0.025 g, 0.17 mmol) in 2 mL of chloroform at room temperature was addedbarium hydroxide monohydrate (0.16 g, 0.86 mmol). This was allowed tostir for 1 hour, filtered and evaporated under reduced pressure. Sulfone2 (0.05 g, 0.143 mmol) in 1 mL of chloroform was added to the residue,the reaction was brought to 65° C. and stirred for 24 hours. The mixturewas cooled and the solvents were removed via evaporation. Methanol/water(90/10, 1 mil) was added and a precipitate formed. The product waswashed with methanol/water, dissolved in methylene chloride andevaporated to yield the amine (0.034 g, mass spec. M+1=378).

Example 82 Preparation of2-(benzylthio)-6-(4-fluorophenoxy)pyrido[2,3-d]pyrimidin-7-amine:

[0383] Step A: Preparation of 4 fluorophenoxy)acetonitrile:

[0384] Iodoacetonitrile (2.14 mL, 29 mmol) was added to a suspension of4-fluorophenol (3.0 g, 27 mmol) and K₂CO₃ (4.85 g, 35 mmol) in 10 mL ofDMF. The reaction was heated to 60° C. for 15 hours then the mixture wascooled, diluted with water and extracted with ethyl acetate-hexane (1:1, 150 mL, 3×). The organic solution was combined and washed with water(200 mL, 2×), and dried (brine, MgSO₄). The solvent was removed underreduced pressure affording 4.1 g of the product.

[0385] Step B: Preparation of2-(benzylthio)-6-(4-fluorophenoxy)pyrido[2,3-d]pyrimidin-7-amine:

[0386] A mixture of the nitrile (prepared in Step A, 1.83 g, 12 mmol),the amino-pyrimidine aldehyde (2.48 g, 10 mmol) and K₂CO₃ (7.0 g, 50mmol) in 30 mL of dimethylformamide was heated in an oil bath at 120° C.for 4 hours. The mixture was cooled, diluted with water and extractedwith ethyl acetate (125 mL, 3×). The organic solution was combined andwashed with water (120 mL, 3×), dried (brine, MgSO₄) and filteredthrough a short column filled with silica. The solvent was removed underreduced pressure and the crude material was purified by columnchromatography (SiO₂, MeOH/CH₂Cl₂, 80/20 to 95/5) affording 1.3 g of theproduct (mass spec. M+1=379, MP=186.2-192.2° C.).

[0387] Displacement of the benzylthio group (or the correspondingsulfoxide or sulfone) with an amine R¹NH₂ as described earlier providescompounds of Formula II where R⁸ and R⁹ are both hydrogen. Furtheralkylation, acylation, sulfonylation, reductive amination etc. providescompounds of Formula II where R⁸ and R⁹ are as described in the Summaryof the Invention.

Example 83 Preparation of6-(2,4-difluorophenoxy)-2-(benzylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0388]

[0389] Step A: Preparation of4-Amino-2-benzylthiopyrimidine-5-carbaldehyde

[0390] To a 1M solution of lithium aluminum hydride (185 mL, 185 mmol)in diethyl ether was added a solution of4-amino-2-benzylthiopyrimidine-5-carboxylate (46 g, 159 mmol) in 500 mLof dry tetrahydrofuran dropwise over a period of 1.5 hours at 0° C. Thereaction mixture was slowly warmed to ambient temperature and thencooled back to 0° C. before carefully quenching with 7 mL of water, 7 mLof 2 M sodium hydroxide solution, followed by 14 mL of water. Theresulting suspension was filtered and the filter residue was washed with2×300 mL of ethyl acetate. The collected fractions were concentrated togive 45.7 g of 4-amino-2-benzylthiopyrimidine-5-methanol as a whitesolid.

[0391] A suspension of 4-amino-2-benzylthiopyrimidine-5-methanol (45.7g) obtained above in 800 mL of methylene chloride was treated withactivated manganese oxide powder (87 g). The reaction mixture wasstirred for 18 hours, then filtered through a pad of celite. The filterresidue was repeatedly washed with a solution of hot methylene chlorideand methanol. The combined fractions were concentrated to give 25 g of4-amino-2-benzylthiopyrimidine-5-carboxaldehyde as a white solid.

[0392] Step B: Preparation of6-(2,4-difluorophenoxy)-2-(benzylthio)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0393] To a mixture of 4-amino-2-benzylthiopyrimidine-5-carboxaldehyde(19.5 g, 80 mmol.) and methyl 2,4-difluorophenoxyacetate (25.6 g, 119mmol) in NMP (50 mL) was added potassium carbonate (16.5 g, 119 mmol).The mixture was heated at 80-90° C. for two days and cooled to roomtemperature. It was added to ice-water (1000 g) and stirred for 1 hour.The solids were filtered, washed with water and ether, and dried to give27 g of the sulfide (Mass spec. M+1=398, MP=240-244° C.).

Example 84

[0394] Preparation of1-tert-Butyl-3-[6-(2,4-difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

[0395] Step A: Preparation of1-tert-Butyl-3-[6-(2,4-difluoro-phenoxy)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-yl]-urea:

[0396] To a solution of the amine IIIe (prepared in similar fashion asdescribed in example 82) (0.32 g, 1.0 mmol) in 5 mL of1-methyl-2-pyrrolidinone at room temperature was added the sodiumhydride (60%, 0.04 g, 1.0 mmol). The mixture was stirred at roomtemperature for 1 hour. t-Butylisocyanate (0.01 g, 0.11 mL, 1.0 mmol)was added by dropwise over a period of three minutes. The dark brownsolution was then stirred for two more hours and poured into 50 mL of 1MHCl and extracted with ethyl acetate (2×, 50 mL). The combined ethylacetate solution was washed with water (3×, 75 mL) and dried (brine,MgSO₄). Evaporation of solvent and purification of product via columnchromatography with silica gel eluting with 10% ethyl acetate indichloromethane gave 0.164 g of desired sulfide.

[0397] Step B: Preparation of1-tert-Butyl-3-[6-(2,4-difluoro-phenoxy)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-yl]-urea:

[0398] To a solution the sulfide (0.164 g, 0.4 mmol) in dichloromethane(50 mL) was added the meta-chioroperbenzoic acid (77% max, 0.19 g, 0.88mmol) at 5° C. The mixture was then stirred at room temperature for 15hours and was poured into 10% aqueous NaHSO₃. The organic solution wasthen washed with 10% aqueous NaHCO₃ and dried (brine, MgSO₄).Evaporation of solvent gave 0.176 g of the sulfone (mass spec. M+1=452).

[0399] Step C: Preparation of1-tert-Butyl-3-[6-(2,4-difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea:

[0400] A solution of the sulfone (0.17 g, 0.4 mmol) and4-amino-tetrahydropyran (0.24 g, 2.3 mmol) in 2 mL of1-methyl-2-pyrrolidinone was heated to 80° C. for 3 hours. The reactiionmixture was cooled, poured into water and extracted with ethyl acetate(2×, 50 mL). The organic solution was washed with water (5×, 50 mL) anddried (brine, MgSO₄). Evaporation of the solvent under reduced pressureand purified via column chromatography (SiO₂, CH₂Cl₂/ethylacetate—50/50) yielded 0.123 g of the desired product (Mass spec.M+1=473, MP=195-201° C.).

Example 85

[0401] Preparation ofN-[6-(2,4-Difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-methanesulfonamide

[0402] Step A: Preparation ofN-[6-(2,4-Difluoro-phenoxy)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-yl]-methanesulfonamide

[0403] To a suspension of the amine IIIe (prepared in similar fashion asdescribed in example 82) (0.32 g, 1.0 mmol) in 10 mL of dichloromethaneat 5° C. was added the trimethylaluminum reagent (2M in Toluene, 0.5 mL,1.0 mmol) dropwise. The dark solution was stirred for 30 minutes atambient temperature. Methanesulfonic anhydride (0.174 g, 1.0 mmol) wasadded and the solution was heated to reflux. Course of reaction wasfollowed by TLC and adddition of more methanesulfonic anhydride wasrequired until completion of reaction. A total of 3.6 equivalents of theanhydride was added and after 5 hours of reflux, the reaction mixturewas poured into aqueous 1M HCl (50 mL) and was extracted with ethylacetate (2×, 50 mL). The solvent was dried (brine, MgSO₄) and afterevaporation the compound was purified via column chromatography (SiO₂,CH₂Cl₂/MeOH—97/3), providing 0.164 g of the sulfonamide-sulfide (Massspec. M+1=399).

[0404] Step B:N-[6-(2,4-Difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-methanesulfonamide

[0405] To a solution of the sulfonamide-sulfide (0.164 g, 0.4 mmol) in20 mL of dichloromethane was added the meta-chloroperbenzoic acid (0.2g, 0.9 mmol). The reaction mixture was stirred at room temperature for15 hours and was washed with 10% aqueous NaHSO₃ and dried (brine andMgSO₄). (Note: do not wash with NaHCO₃, the sulfone is base sensitive).The solvent was evaporated under reduced pressure and thissulfonamide-sulfone (0.4 mmol) and 4-amino-tetrahydropyran (0.5 g) in1.0 mL of 1-methyl-2-pyrrolidinone was heated to 100° C. for 12 hoursafter which the solvent was evaporated under high vacuum and thecompound was purified via column chromatography (SiO₂,CH₂Cl₂/MeOH—97/3), providing 90 mg of desired product (Mass spec.M+H=452, MP=199-204° C.).

Example 86 Preparation of6-(2,4-difluorophenoxy)-2-{[(1S)-2-fluoro-1,2-dimethylpropyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0406]

[0407] To the compound obtained in the Example 53 (free base, 0.28 g) inmethylene chloride (5 mL) at −78° C. was added DAST (Aldrich, 0.14 mL).The reaction mixture was slowly warmed up to room temperature. It waspartitioned between methylene chloride and water. The organic layer wasseparated and washed with saturated aqueous sodium carbonate, dried, andconcentrated to give the crude product. Preparative TLC (silica gel, 45%EtOAc/hexanes) gave the pure product (0.16 g). It was converted to thehydrochloride salt by treatment with 1M HCl in ether to giveRO3310297-001 (Mass spec. M+1=393, MP=196-197.2° C.).

Example 87 Preparation of6-(2,4-Difluoro-phenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one

[0408] Step A: Preparation of6-(2,4-Difluoro-phenoxy)-8-isopropyl-2-phenylmethanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0409] The above sulfide (2.2 g, 5.5 mmol), potassium carbonate (0.84 g,6.1 mmol), and 2-iodopropane (0.58 mL, 5.8 mmol) in dry DMF (5 mL) werestirred at room temperature overnight. Aqueous TM work up gave the crudesulfide. It was dissolved in THF (50 mL) and treated with oxone (8 g) inwater (50 mL) at 0-5. The mixture was then slowly warmed to roomtemperature and stirred for additional 5 hours. Aqueous work up gave thecrude sulfone.

[0410] Step B: Preparation of6-(2,4-Difluoro-phenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one

[0411] The above sulfone (0.93 g, 2.05 mmol),(3S)-3-amino-2-methylbutan-2-ol hydrochloride salt (0.54 g, 4 mmol) andtriethylamine (1 mL) in isopropyl alcohol (10 mL) were refluxed for 10hours. Aqueous work up gave the crude product. After columnchromatography (silica gel, 35%-45% EtOAc/hexanes) the pure product(0.386 g) was obtained. It was converted to its hydrochloride salt bythe treatment with 1M HCl (in ether) and recrystallized from isopropylalcohol to gave RO3310294-001 (0.29 g) (Mass spec. M+1=419, MP=200-202°C.).

Example 88 Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyridin-7(8H)-one

[0412] Step A: Preparation of 6-Chloro-4-methylamino-nicotinic AcidEthyl Ester

[0413] 4,6-dichloro-3-nicotinic acid ethyl ester (Specs, 7.37 g, 33.5mmol) was stirred with aqueous methyl amine (40%, 14.5 mL) inacetonitrile (50 mL) at 0-5° C. and then room temperature for 6 hours.The mixture was concentrated and added EtOAc. The organic layer waswashed with brine (2×), dried and evaporated to give the desired product(7.12 g; MP=61.4-63.1° C.).

[0414] Step B: Preparation of6-Chloro-4-methylamino-pyridine-3-carbaldehyde

[0415] Step b: To the above ester (7.1 g, 33.2 mmol) in THF (100 mL) wasslowly added LAH (1.0 M in THF, 70 mL) at −78° C. and stirred for 3hours. The temperature was slowly raised to −10° C. and TLC indicatedthat the ester was consumed. MeOH/EtOAc (5 ml each) was added to destroyexcess LAH and the mixture was warmed to room temperature. Water (50 mL)and EtOAc (500 mL) were added and filtered through a pad of celite. Thefiltrate was separated and dried. The crude product was further purifiedby column chromatography (silica gel, 40-75% EtOAc/hexanes and then 5%MeOH/CH₂Cl₂) to give 3.3 g of solids (Mass spec. M+1=173.1,MP=168.8-169.6° C.).

[0416] The alcohol obtained (3.2 g) was stirred with MnO2 (16.2 g) inmethylene chloride (800 mL) at room temperature for two hours. Themixture was filtered through a pad of celite and washed with EtOAc. Thefiltrate was concentrated to give the aldehyde (2.8 g, MP=77.2-80.8°C.).

[0417] Step C: Preparation of7-Chloro-3-(2,4-difluoro-phenoxy)-1-methyl-]H-[1,6]naphthyridin-2-one

[0418] The aldehyde obtained above (1.8 g) was heated with methyl2,4-difluorophenoxyacetate (4.1 g) and potassium carbonate (4.1 g) inNMP (20 mL) at 70° C. for two days. EtOAc (200 mL) was added and washedwith brine (3×), dried and concentrated to give the crude product.Tituration with hexanes gave 3.07 g of white solids (Mass spec. M+1=323,MP=168-170.5° C.

[0419] Step D: Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyridin-7(8H)-one

[0420] The product obtained above (2.06 g, 6.4 mmol) was heated with4-amino-tetrahydropyran (3.4 g, 33.6 mmol) at 150-160° C. for threedays. The mixture was cooled to room temperature and stirred with EtOAc(200 mL) and brine (50 mL). The organic layer was separated, dried, andconcentrated. The crude product obtained was purified by columnchromatography (40-60% EtOAc/hexanes) to 1.65 g of solids. They weredissolved in CH₂Cl₂/MeOH (5 mL each) and treated with 4.5 mL of 1M HClin ether. The solvents were removed and the resulting solids wererecrystallized from isopropyl alcohol to 1.3 g of white crystals (Massspec. M+1=388.2, MP=237.5-239° C.).

Example 89 Preparation of8-Amino-6-(2,4-difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one

[0421] Step A: Preparation of8-Amino-2-benzylsulfanyl-6-(2,4-difluoro-phenoxy)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0422] To a solution of the sulfide (see Example 83 for preparation)(2.67 g, 6.72 mmol) in DMF (120 mL) at 0° C. with stirring was added 60%NaH (375 mg, 1.4 eq) in one portion. The resulting mixture was stirredat 0° C. for 30 minutes. Then diphenyl phosphinyl-O-hydroxylamine (Tet.Let., vol.23, No. 37, 3835-3836, 1982) (2.34 g, 1.5 eq) was added in oneportion. After about one minute, the mixture became very thick anddifficult to stir. TLC analysis indicated that all of the starting NHsulfide was consumed. Added ethyl acetate (650 mL) and water (250 mL) tothe reaction, partitioned and separated the layers. The ethyl acetatelayer was further washed with water (4×200 mL) and then finally washedwith brine (1×200 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated. Pumped under high vacuum to give thehydrazido sulfide as a dark tan powder (2.683 g, (M+H)⁺=413,m.p.=179.3-182.3° C.).

[0423] Step B: Preparation of8-Amino-6-(2,4-difluoro-phenoxy)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0424] To the sulfide (820 mg, 1.99 mmol) and 4-aminotetrahydropyran(500 mg, 2.5 eq) was added NMP (0.8 mL) and the resulting mixture washeated with stirring at 150° C. for 24 hours. By TLC, the startinghydrazido sulfide was consumed. Ethyl acetate (175 mL) and water (50 mL)were added and the layers were partitioned and then separated. Theaqueous layer was further extracted with ethyl acetate (1000 mL) and thecombined ethyl acetate layers were washed with water (2×200 mL).Finally, the organic layer was washed with brine (1×150 mL) and then theethyl acetate layer was dried over magnesium sulfate, filtered andconcentrated to give 882 mg of the crude product. Purification byPreparative Thin Layer Chromatography eluting with 6% methanol indichloromethane gave the free amine as a dark tan powder (44 mg). Thefree amine was taken up in dichloromethane (15 mL) and then 1M HCl indiethyl ether (0.17 mL, 1.5 eq) was added with stirring. Stirred for 5minutes and then the solvent was removed under reduced pressure at 50°C. Dried under high vacuum at 56° C. for 24 hours to give the desiredproduct (43 mg, (M+H)⁺=390) as a tan powder.

Example 90 Preparation of6-(2,4-Difluoro-phenoxy)-8-isopropylamino-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one

[0425] Step A: Preparation of2-Benzylsulfanyl-6-(2,4-difluoro-phenoxy)-8-isopropylamino-8H-pyrido[2,3-d]pyrimidin-7-one:

[0426] To the hydrazido sulfide (300 mg, 0.73 mmol) in methanol (70 mL)and acetic acid (16 mL) was added acetone (0.16 mL) followed by sodiumcyanoborohydride (55 mg, 1.2 eq). The resulting mixture was stirred atroom temperature for 24 hours. The next day the reaction mixture waspoured in to saturated sodium bicarbonate (100 mL) and then extractedwith ethyl acetate (2×100 mL). The ethyl acetate extracts were washedwith brine (1×50 mL) and then dried over magnesium sulfate, filtered andconcentrated to give 323 mg of crude product. Purification byPreparative Thin Layer Chromatography eluting with 30% ethyl acetate inhexanes gave the desired compound (64 mg, (M+H)⁺=455).

[0427] Step B.: Preparation of2-Benzylsulfinyl-6-(2,4-difluoro-phenoxy)-8-isopropylamino-8H-pyrido[2,3-d]pyrimidin-7-one

[0428] To the N-isopropyl hydrazido sulfide (64 mg, 0.141 mmol) in THF(10 mL) at 0° C. with stirring was added a solution of oxone (130 mg,1.4 eq) in water (10 mL) dropwise. After the addition was complete, theresulting mixture was stirred from 0° C. to room temperature overnight.The next day the reaction was complete by TLC. Ethyl acetate (75 mL) andwater (25 mL) were added and then partitioned and separated the layers.Washed further with water (2×25 mL) and finally washed with brine (1×75mL). The organic layer was dried over magnesium sulfate, filtered,concentrated and pumped to give the N-isopropyl hydrazido sulfoxide (74mg, (M+H)⁺=471).

[0429] Step C: Preparation of6-(2,4-Difluoro-phenoxy)-8-isopropylamino-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0430] The sulfoxide (74 mg, 0.157 mmol), 4-aminotetrahydropyran (80 mg,5 eq) and NMP (0.1 mL) were mixed together and heated ad 80° C. withstirring for 30 minutes. By TLC the reaction was complete and was cooledto room temperature. Ethyl acetate (35 mL) and water (25 mL) were addedand then partitioned and separated the layers. The organic layer wasfurther washed with water (2×25 mL) and finally with brine (1×25 mL).Then dried the ethyl acetate layer over magnesium sulfate, filtered andconcentrated. Pumped under high vacuum to give 75 mg of crude product.Purification by Preparative Thin Layer Chromatography eluting with 75% eethyl acetate in hexanes gave the desired compound as the free amine (39mg). The free amine was taken up in dichloromethane (5 mL) and withstirring was added 1M HCl in diethyl ether (0.14 mL, 1.2 eq). Theresulting mixture was stirred for 5 minutes. Then the solvent wasremoved under reduced pressure at 50° C. Dried under high vacuum at 56°C. for 24 hours to give the title compound as an off-white powder (39mg, (M+H)⁺=432).

Example 91 Preparation of6-(2,4-Difluoro-phenoxy)-8-[N-methyl-(N-3-methyl-butyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one

[0431] Step A: Preparation of2-Benzylsulfanyl-6-(2,4-difluoro-phenoxy)-8-N-isobutylamino-8H-pyrido[2,3-d]pyrimidin-7-one

[0432] To a mixture of the hydrazido sulfide (1 g, 2.52 mmol) inmethanol (200 ml) and acetic acid was added isobutyraldehyde (0.3 mL,1.3 eq) followed by sodium cyanoborohydride (159 mg, 1 eq). Theresulting mixture was stirred at room temperature for 3.5 hours. Thenadded ethyl acetate (500 mL) and washed with saturated sodiumbicarbonate (5×200 mL) until slightly basic. Finally washed with brine(1×150 mL) and the organic layer was dried over magnesium sulfate,filtered, concentrated and pumped to give the crude product (1.083 g) asa tan solid. Purification by Flash Column Chromatography on silica geleluting with 15% ethyl acetate in hexanes gave the desired product as afoamy solid (487 mg, (M+H)⁺=469, m.p.=132.1-133.9° C.).

[0433] Step B: Preparation of2-Benzylsulfanyl-6-(2,4-difluoro-phenoxy)-8-(N-isobutyl-N-methyl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one

[0434] To the N-isobutyl hydrazido sulfide (100 mg, 0.213 mmol) inmethanol (10.5 mL) at 0° C. was added acetic acid (3 mL) followed by 37%formaldehyde_((aq)) (25 μL, 1.6 eq) and then sodium cyanoborohydride (20mg, 1.4 eq). The resulting mixture was stirred from 0° C. to roomtemperature overnight. The next day there was only a trace of startingmaterial by TLC. The reaction was poured into saturated sodiumbicarbonate (150 mL) and then extracted with ethyl acetate (3×75 mL).The combined ethyl acetate layers were washed with brine (1×50 mL) andthen dried over magnesium sulfate, filtered and concentrated. This crudematerial was purified by Preparative Thin Layer Chromatography elutingwith 20% ethyl acetate in hexanes to afford the desired compound as awhite foamy solid (96 mg, (M+H)⁺=483).

[0435] Step C. Preparation of2-Benzylsulfinyl-6-(2,4-difluoro-phenoxy)-8-(N-isobutyl-N-methyl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one

[0436] To the sulfide (96 mg, 0.199 mmol) in THF (10 mL) at 0° C. withstirring was added dropwise a solution of oxone (185 mg, 1.5 eq) inwater (10 mL). After addition was complete, the resulting mixture wasstirred from 0° C. to room temperature overnight. By TLC the reactionwas complete the next day. Added ethyl acetate (75 mL) and washed withwater (4×30 mL) and finally washed with brine (1×30 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated togive the desired compound as a white foamy solid (95 mg, (M+H)⁺=499).

[0437] Step D: Preparation of6-(2,4-Difluoro-phenoxy)-8-[N-methyl-(N-3-methyl-butyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0438] The N-isobutyl, N-methyl hydrazido sulfoxide (95 mg, 0.191 mmol),4-amino tetrahydropyran (97 mg, 5 eq) and NMP (0.1 mL) were mixedtogether and heated at 80° C. with stirring for 30 minutes. By TLC, allof the starting sulfoxide was consumed. Cooled to room temperature andadded ethyl acetate (35 mL) and water (25 mL). Partitioned and separatedthe layers and subsequently washed with water (2×25 mL) followed withbrine (1×25 mL). The organic layer was dried over magnesium sulfate,filtered concentrated and pumped. Purification by Preparative Thin LayerChromatography eluting with 40% ethyl acetate in hexanes gave thedesired product as the free amine (82 mg). The free amine (82 mg) wastaken up in dichloromethane (5 mL) and then added 1M HCl in diethylether (0.2 mL, 1.2 eq). The resulting mixture was stirred for 5 minutesand then the solvent was removed under reduced pressure at 50° C. Driedunder high vacuum at 56° C. for 24 hours to give the title compound (60mg, (M+H)⁺=460) as an off-white powder.

Example 92 Preparation of6-(2,4-Difluoro-phenoxy)-8-N,N-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0439] Step A: Preparation of2-Benzylsulfanyl-6-(2,4-difluoro-phenoxy)-8-N,N-dimethylamino-8H-pyrido[2,3-d]pyrimidin-7-one:

[0440] The hydrazido sulfide (1.5 g, 3.64 mmol) was taken up in methanol(200 mL) and acetic acid (60 mL) and then added 37% formaldehyde_((aq))(0.5 mL, 4 eq) followed by sodium cyanoborohydride (458 mg, 2 eq). Theresulting mixture was stirred at room temperature overnight. The nextday there was still some starting sulfide remaining, so additional 37%formaldehyde_((aq)) (0.5 mL, 4 eq) was added and the reaction wasstirred at room temperature for one more day. On the second day, thereaction was complete by TLC. Added ethyl acetate (300 mL) and saturatedsodium bicarbonate (150 mL) and partitioned. Then separated the layersand washed with more saturated sodium bicarbonate (3×150 mL) untilslightly basic. Finally washed with brine(1×150 mL) and the organiclayer was dried over magnesium sulfate, filtered, concentrated andpumped to give crude product (1.93 g). Purification by Flash ColumnChromatography on silica gel eluting with 15% ethyl acetate in hexanesafforded the desired product as a foamy off-white solid (740 mg,(M+H)⁺=441, m.p.=63.0-66.0° C.).

[0441] Step B.: Preparation of2-Benzylsulfinyl-6-(2,4-difluoro-phenoxy)-8-N,N-dimethylamino-8H-pyrido[2,3-d]pyrimidin-7-one:

[0442] To the sulfide (725 mg, 1.65 mmol) in THF (30 mL) at 0° C. withstirring was added dropwise a solution of oxone (1.01 g, 1 eq) in water(20 mL). After addition was complete, the resulting mixture was stirredfrom 0° C. to room temperature for 6 hours. Then added ethyl acetate(100 ml) and washed with water (3×50 mL) followed by brine (1×50 mL).The organic layer was dried over magnesium sulfate, filtered,concentrated and pumped the give the desired compound as a foamy whitesolid (727 mg, (M+H)⁺=457, m.p.=80.5-89.9° C.).

[0443] Step C: Preparation of6-(2,4-Difluoro-phenoxy)-8-N,N-dimethylamino-2-(teirahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0444] The sulfoxide (308 mg, 0.675 mmol), 4-amino tetrahydropyran (205mg, 3 eq) and NMP (0.3 mL) were mixed together and heated at 80° C. withstirring for 30 minutes. By TLC, the reaction was complete. Ethylacetate (35 mL) and water (25 ml) were added, partitioned and separatedthe layers. The organic layer was washed with water (2×25 mL) andfinally with brine (1×25 mL). Dried the ethyl acetate layer overmagnesium sulfate, filtered, concentrated and pumped to give the crudeproduct (571 mg). Purification by Preparative Thin Layer Chromatographyeluting with 70% ethyl acetate in hexanes afforded the product as thefree amine (185 mg). The free amine was taken up in dichloromethane (20mL) and then 1M HCl in diethyl ether (1.2 eq, 0.5 mL) was added. Theresulting mixture was stirred for 5 minutes and then the solvent wasremoved under reduced pressure at 50° C. Dried under high vacuum at 56°C. for 24 hours to give the title compound as an off-white powder (195mg, (M+H)⁺=418, m.p.=126.4-131.0° C.).

Example 93 Preparation of6-(2,4-Difluoro-phenylamino)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one:

[0445] Step A: Preparation of (2,4-Difluoro-phenyl)-carbamic Acid BenzylEster

[0446] The 2,4 difluoro aniline (5.06 ml, 49.6 mmole) put into asolution of 10% NaOH (76 ml). Cooled in an ice bath and added benzylchloroformate (7.85 ml, 55 mmole). After stirring for for 2 hours theproduct was filtered, stirred with hexane, dried. Yield 9.4 g

[0447] Step B: Preparation of[Benzyloxycarbonyl-(2,4-difluoro-phenyl)-amino]-acetic Acid Methyl Ester

[0448] The CBZ protected aniline (7.89 g 30 mmole) dissolved in1-methyl-2-pyrrolidinone (NMP) and cooled in an ice bath to 0°. To thissolution was added sodium hydride (1.3 g 60% oil dispersion, 32.5mmole), this was stirred at for 30 minutes. To this solution was addedmethyl bromoacetate (3.0 ml, 31 mmole), this solution was allowed towarm to room temperature and stirred for 12 hours. Added to water andextracted with ethyl acetate, washed 5 times with water, dried(magnesiun sulfate) and evaporated to dryness. The product was purifiedby column chromatography (80:20 hexane:ethyl acetate) to give theproduct. Yield 8.2 g

[0449] Step C: Preparation of(2,4-Difluoro-phenyl)-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamicacid benzyl ester

[0450] To a solution of the aldehyde (1.69 g, 10 mmole) in NMP and theCBZ protected aniline (3.5 g, 10.5 mmole) was added potassium carbonate(2.0 g, 14.5 mmole) and heated at 120° for 12 hours. Reaction mixturecooled to room temperature and added to water. Extracted with ethylacetate and washed 5 times with water, dried (MgSO₄) and evaporated todryness. Product purified by column chromatography (75:25 EtOAc:Hexane).Yield 1.9 g (M+H)⁺469

[0451] Step D: Preparation of(2,4-Difluoro-phenyl)-(8-methyl-2-methylsulfonyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamicAcid Benzyl Ester

[0452] To a solution of the sulfide (8.5 g, 18 mmole) in CH₂Cl₂ (100 ml)was added meta chloro perbenzoic acid (9.0 g˜75%, 39 mmole), and stirredat room temperature for 12 hours. The reaction solution was washed witha 10% solution of NaSO₃, then three timew with a 10% solution of NaHCO₃,dried (MgSO₄), and evaporated to dryness. The crude product was stirredwith ethyl ether (100 ml) for an hour, filtered, and dried. Yield 7.9 g

[0453] Step E: Preparation of(2,4-Difluoro-phenyl)-[2-(2-hydroxy-,1,1-dimethyl-ethylamino)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-carbamicAcid Benzyl Ester

[0454] The sulfone (0.5 g 1 mmole) was combined with the2-amino-2-methyl-1-propanol (0.5 g, 5.5 mmole) and 0.5 ml NMP, thissolution was heated at 80° for 1 hour. Cooled to room temperature, addedMeOH (2 ml) and water (4 ml), stirred for one hour, filtered to give theproduct as a solid. Yield 450 mg, (M+H)⁺510

[0455] Step F: Preparation of6-(2,4-Difluoro-phenylamino)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0456] The CBZ protected amine (450 mg, 0.8 mmole) dissolved in EtOH (20ml) to this added 5% Pd/carbon (50 mg) and hygrogenated at atmosphericpressure. After 12 hours filtered through celite, evaporated to dryness.This material suspended in MeOH, and acidified with hydrochloric acid(1.0M/Et₂O, 1 equivalent), stirred for 20 minutes, evaporated underreduced pressure, stirred with a mixture of Et₂O/MeOH, for 2 hours,filtered to give the hydrochloride salt. Yield 140 mg MP216-217.9°. MS(M+H)⁺376.

Example 94 Preparation of6-[(2,4-Difluoro-phenyl)-methyl-amino]-8-methyl-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0457] Step A: Preparation of[(2,4-Difluoro-phenyl)-methyl-amino]-acetic Acid Methyl Ester

[0458] To a mixture of the 2,4-Difluoro-N-methylaniline (AvacadoResearch Chemical, Heysham UK) (1.43 g, 10 mmole) in NMP, and K₂CO₃, wasadded methyl bromoacetate (0.945 ml, 10 mmole) and stirred at roomtemperature for 24 hours. The reaction mixture was added to water andextracted with ethyl acetate (3×50 ml), the organic extracts were washed6× with water, dried (MgSO₄) amd evaporated to give the product as aoil.

[0459] Yield 2.0 g

[0460] Step B: Preparation of6-[(2,4-Difluoro-phenyl)-methyl-amino]-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0461] A mixture of 4-methylamino-2methylthipyrimidine-5-carboxaldehyde(915 mg, 5 mmole) and the aniline (131 g, 5.1 mmole) and K₂CO₃ (1.5 g,10.8 mmole)in 10 ml of NMP was heated at 120°. After 12 hours thereaction mixture was cooled to room temperature and added to 100 ml ofwater. The resultant mixture was extracted with EtOAc, (3×, 100 ml), andthe organic layer was with water 6×, dried (MgSO₄) and evaporated underreduced presure. The product residue was stirred with ether (50 ml) for1 hor, filtered to yield the product as a solid. Yield 1.07 g MS(M+H)⁺349

[0462] Step C: Preparation of6-[(2,4-Difluoro-phenyl)-methyl-amino]-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0463] The sulfide (1.0 g, 2.8 mmole)was disolved in 25 ml ofdichloromethane, to this solution was added 3-chloroperbenzoic acid(77%, 1.4 g, 6.2 mmole). This solution was stirred at room temperaturefor 6 hours, then washed with an aqueous sodium sulfite solution (2×, 10ml) and with a saturated solution of sodium bicarbonate (3×, 10 ml). Theorganic solution then dried (MgSO₄), and evaporated to a solid resiue.This residue was stirred with ether (25 ml), filtered and dried to givethe sulfone as a solid. Yield 870 mg MS (M+H)₊381

[0464] Step D: Preparation of6-[(2,4-Difluoro-phenyl)-methyl-amino]-8-methyl-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one

[0465] A mixture of the sulfone (0.4 g, 1.05 mmole) and4-amino-tetrahydropyran (0.35 g, 3.47 mmole) and 0.3 ml of NMP heated at80° for 1 hour. Cooled to room temperature, added 1.0 ml MeOH, and 2.0ml of water, stirred at room temperature for 1 hour, and filtered,washed with water and dried, to give the product as a solid. The productwas suspended in MeOH, and made acidic with hydrochloric acid (1.0M/Et₂O1 equivalent) and stirred for an hour. The organic solvent wasevaporated, the residue was stirred with a mixture of MeOH/Et₂O for anhour, filtered to give the product as a hydrochloride salt. Yield 0.358g MP197-198.5°MS (M+H)⁺402

Example 95 Preparation of6-(2,4-Difluorophenoxy)-8-ethyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0466] Step A: Preparation of Ethyl4-ethylamino-2-methyl-thiopyrimidine-5-carboxylate

[0467] To a solution of 25 g (107 mmole) ethyl4-chloro-2-methylthio-5-pyrimiinecarboxylate in 250 ml oftetrahydrofuran was added 47 ml (337 mmole) and 43 ml of 70% ethylaminesolution (668 mmole). The mixture was stirred at room temperature for 4hours. Evaporated to dryness, this material dissolve in a mixture ofethyl acetate/water, washed twice with 10% NaHCO₃ solution, dried(MgSO₄), evaporated to dryness to give the product as a solid. Yield24.1 g

[0468] Step B: Preparation4-ethylamino-2-methylthiopyrimidine-5-methanol

[0469] A solution of the ethyl4-ethylamino-2-methylthio-pyrimidinecarboxylate (24.1 g, 100 mmole) intetrahydrofuran (250 ml) was cooled in an ice bath to 0°. To thissolution was carefully added I small portions over an hour lithiumaluminum hydride (4.3 g, 113 mmole), one hour after addition is completewater is slowly added (4.3 ml), then a solution of NaOH (4.3 ml, 15%),then an additional 13 ml of water added, stirred for 1 hour. Theresulting suspension was filtered, the filter residue washed twice with100 ml of tetrahydrfuran. This solution was evaporated under reducedpressure. The residue stirred with 150 ml Et₂O, filtered, dried. Yield19.1 g.

[0470] Step C: Preparation of4-ethylamino-2-methylthiopyrimidine-5-carboxaldehyde

[0471] To a solution of 4-ethylamino-2-methylthiopyrimidine-5-methanol(19.1 g, 96 mmole) in 1000 ml of dichloromethane was added 87 g ofmanganese dioxide. The resulting suspension was stirred for 20 hours,filtered through celite. The residue was washed twice with 100 ml ofdichloromethane, the combined filtrate and washings was evaporated underreduced pressure to give the product as a solid. Yield 12.8 g

[0472] Step D: Preparation of6-(2,4-difluorophenoxy)-8-ethyl-2-methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0473] To a mixture of4-ethylamino-2-methylthiopyrimidine-5-carboxalehyde (5.0 g, 25.5 mmole)and the phenoxy acetate (6.0 g, 29.7 mmole) in 50 ml of NMP was addedK₂CO₃ (6.0 g, 43.4 mmole) and heated at 120°. After 2 hours anadditional 1.5 g of the ester was added and heated an additional 2hours. At this time and additional 1.5 g of the ester and 2.0 g K₂CO₃was added to the reaction, after an additional 2 hours the reaction wascooled to room temperature. The reaction mixture was added to water (300ml) and stirred for 2 hours. Filtered, and washed with ethyl ether,dried.

[0474] Yield 8.7 g MP 122-127.90 MS (M+H)⁺350

[0475] Step E: Preparation of6-(2,4-difluorophenoxy)-8-ethyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0476] The sulfide (8.7 g, 24.9 mmole) was dissolved in 100 ml ofdichloromethane and 3-chloroperbenzoic acid (77% 11.5 g 50 mmole) wasadded. The mixture was stirred at room temperature for 8 hours, thenwashed with sodium sulfite solution (2×, 75 ml) followed by saturatedaqueous sodium bicarbonate (3×, 75 ml). The organic solution was thendried (MgSO₄) and evaporated. The resultant solid was stirred with etherfor 1 hour, and filtered to yield the sulfone as a white solid. Yield6.9 g MP 128-129.10 MS (M+H)⁺381

[0477] Step F: Preparation of6-(2,4-difluorophenoxy)-8-ethyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0478] A mixture of the sulfone (6.0 g, 15.7 mmole) and4-amino-tetrahyropyran (5.0 g, 49.5 mmole) and 6.0 ml of NMP was heatedat 80°. After 1 hour cooled to room temperature, added 12ml of MeOH, and24 ml of water, stirred for 1 hour. The suspension was filtered, washedwith water (1.0M Et₂O I equivalent), the mixture was stirred for 1 hourand evaporated. The solid residue was stirre with a mixture of MeOH/Et₂Ofor one hour, filtered, washed with ether, and dried. Yield 5.9 gMP199.1-205.9° MS (M+H)⁺403

Example 96 Preparation of6-(2,4-difluorophenoxy)-8-ethyl-2-(3-hydroxy-tetrahydro-pyran-4ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0479]

[0480] A mixture of the sulfone (see example 95 for preparation) (0.50g, 1.31 mmol) and trans-4-amino-3-hydroxy-tetrahydropyran (0.23 g, 1.97mmol) (see following ref for preparation: (a) Marquis, Robert W et al J.Med. Chem. (2001), 44(5), 725-736. (b) Gribble, Andrew D et al PCT Int.Appl. (1998), 74 pp. (c) Mochalin, V. B et al Zh. Org. Khim. (1971),7(4), 825-8). in 2 mL of 1-methyl-2-pyrrolidinone was heated at 100° C.for 12 h. The reaction mixture was cooled, ethyl acetate (15 mL) wasadded and the organic solution was washed with water (3×, 15 mL), brineand then dried (MgSO₄). Evaporation of the solvent under reducedpressure and column chromatography (CH₂Cl₂/methanol—97/3) afforded 120mg of product (mpt. 174.9-176.3° C., MS (M+H)=419)

Example 97 Preparation of6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1,3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one:

[0481] Step A: Preparation of 4-Hydroxy-4-methyl-pentan-2-one Oxime

[0482] A mixture of 4-hydroxy-4-methyl-2-pentanone (10.0 g, 85.7 mmole)and hydroxylamine hydrochloride (22.17 g, 343 mmole) in 90 ml of waterwas stirred vigorously at room temperature. To this solution was addedslowly over a period of an hour solid sodium bicarbonate (26.8 g, 343mmole). After 3 hours the reaction mixture was extracted with ethylacetate (3×, 100 ml), dried (MgSO₄) and evaporated under reducedpressure, to give the product as an oil. Yield 11.2 g

[0483] Step B: Preparation of 4-Amino-2-methyl-pentan-2-ol

[0484] The oxime (11.2 g, 85 mmole) was dissolved in 150 ml of ethanol,to this was added a slurry of 20 ml of 50% Raney Nickel/water, and putonto a Parr hydrogenator at 50 psi. After 6 hours the reaction mixturewas filtered through celite, and evaporated to give the amine as an oil.Yield 9.9 g

[0485] Step C: Preparation of6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1,3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0486] A mixture of the sulfone (1.0 g, 2.7 mmole), the4-amino-2-hydroxy-2methyl pentane (1.0 g, 8.5 mmole) and 1.0 ml of NMPheated at 80° for 2 hours. The reaction mixture was cooled, and added towater, extracted with ethyl acetate (3×, 75 ml), washed with water (6×,75 ml), dried (MgSO₄), and evaporated. The residue was purified bycolumn chromatography (SiO₂, CH₂Cl₂/MeOH—95/5) to give the pure product.The residue was suspended in MeOH and acidified with hydrochloric acid(Et₂₀₁HCl, 1.0M, 1 equivalent), stirred for 30 minutes, then evaporated.The residue was stirred in a mixture of methanol/ether for 1 hour,filtered and dried to give the product as a white solid. Yield 818 mg MP158.9-161°, Ms (M+H)⁺405

[0487] By following the above procedure and resolving the amino alcoholin step B prior to use in step C may also be prepared:

[0488] 6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1(S),3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, and

[0489] 6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1(R),3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one.

Example 98 Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(3-hydroxy-tetrahydro-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0490]

[0491] A mixture of sulfone 5 (0.70 g, 1.4 mmol) andtrans-4-amino-3-hydroxy-tetrahydropyran (0.33 g, 2.85 mmol) (seefollowing ref for preparation: (a) Marquis, Robert W et al J. Med. Chem.(2001), 44(5), 725-736. (b) Gribble, Andrew D et al PCT Int. Appl.(1998), 74 pp. (c) Mochalin, V. B et al Zh. Org. Khim. (1971), 7(4),825-8). in 2 mL of 1-methyl-2-pyrrolidinone was heated at 100° C. for 12h. The reaction mixture was cooled, ethyl acetate (20 mL) was added. Theorganic solution was then washed with water (3×, 30 mL) and dried(MgSO₄). Evaporation of the solvent and thin layer chromatography(CH₂Cl₂/EtOAc—95/5) afforded 0.25 g of the product. Addition ofhydrochloric acid (1.0M/Et₂O, 1.2 equivalents) gave the salt which wasfiltered and dried to give 185 mg of desired product (mpt. 226.4-227.7°C., MS (M+H)=405)

Example 99 Preparation of6-(2-fluorophenoxy)-2-[(5-hydroxypyrazol-3-yl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0492]

[0493] A mixture of sulfone 2 (0.05 g, 0.142 mmol), 3-amino-5-hydroxypyrazole (0.017 g, 0.0172 mmol) in 1.0 ml DMF was heated to 65° C. for42 hours and cooled Evaporation of the solvents yielded a residue whichwas purified via chromatography (Supelco Supelclean™, Sigma Aldrich, St.Louis, Mo., LC-Si SPE tube, 6 mL/1 g —CH₂Cl₂ to 4% MeOH/CH₂Cl₂ andMS/HPLC— (0.0013 g, mass spec. M+1=369)

Example 100 Preparation of6-(2-fluorophenoxy)-2-[(pyridin-2-yl-methyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0494]

[0495] A mixture of sulfone 2 (0.05 g, 0.142 mmol),4-(aminomethyl)pyridine, (0.019 g, 0.0172 mmol) in 1 ml DMF was heatedto 65° C. for 18 hours. The cooled reaction mixture was diluted with 2mL each H₂O and EtOAc and partitioned between the two phases. The EtOAcwas filtered through a plug of 0.5 g of MgSO₄, evaporated and purifiedvia Supelco Supelclean™ LC-Si SPE tube, 6 mL (1 g) (CH₂Cl₂ to 2%MeOH/CH₂Cl₂) and MS/HPLC (0.0068 g, mass spec. M+1=378).

Example 101 Preparation of2-{[(1,5-Dimethyl-1H-pyrazol-4-yl)methyl]amino}-6-(2-fluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0496]

[0497] (1,5-Dimethyl-1H-pyrazol-4-yl)methylamine HCl.H₂O (0.031 g, 0.172mmol) was treated with 0.0172 ml 1M KOH/MeOH and evaporated. The aminewas mixed with sulfone 2 (0.05 g, 0.142 mmol) in 1 ml DMF at 65° C. for18 hours. The cooled reaction mixture was diluted with 2 mL each H₂O andEtOAc and partitioned between the two phases. The EtOAc was filteredthrough a plug of 0.5 g MgSO₄, evaporated and the resulting mixture waschromatographed via Supelco Supelclean™ LC-Si SPE tube 6 mL (1 g)(CH₂Cl₂ to 2% MeOH/CH₂Cl₂). (0.005 g, mass spec. M +1=395)

Example 102 Preparation of2-{[(1,3-Dimethyl-1H-pyrazol-4-yl)methyl]amino}-6-(2-fluorophenoxy-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0498]

[0499] (1,3-Dimethyl-1H-pyrazol-4-yl)methylamine 1.8 HCl.1.5H₂O (0.037g, 0.172 mmol) was treated with 0.0172 ml 1M KOH/MeOH and evaporated.The free amine was mixed with sulfone 2 (0.05 g, 0.142 mmol) in 1 ml DMFat 65° C. for 18 hours. The cooled reaction mixture was diluted with 2mL each H₂O and EtOAc and partitioned between the two phases. Theorganic phase was filtered through a plug of 0.5 g MgSO₄ and evaporated.The resulting mixture was chromatographed via Supelco Supelclean™ LC-SiSPE tube 6 mL (1 g) (CH₂Cl₂ to 2% MeOH/CH₂Cl₂). (0.0266 g mass spec.M+1=395)

Example 103 Preparation of6-(2-fluorophenoxy)-2-{[(3-methyl-isoxazol-5-yl)methyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0500]

[0501] (3-Methyl-isoxazol-5-yl)methylamine HCl (0.026 g, 0.172 mmol) wastreated with 0.0172 ml 1M KOH/MeOH and evaporated. The free amine wasmixed with sulfone 2 (0.05 g, 0.142 mmol) in 1 ml DMF at 65° C. for 18hours. The cooled reaction mixture was diluted with 2 mL each H₂O andEtOAc and partitioned between the two phases. The EtOAc was evaporatedand the resulting mixture was chromatographed via Supelco Supelclean™LC-Si SPE tube 6 mL (1 g) (CH₂Cl₂ to 2% MeOH/CH₂Cl₂). (0.0094 g massspec. M+1=382)

Example 1042-{[1-(Hydroxymethyl)cyclohexyl]amino}-6-(2-methylbenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0502]

[0503] A mixture of sulfone (prepared in similar fashion to sulfone 8)(0.05 g, 0.146 mmol), (1-aminocyclohexyl)methanol (0.038 g, 0.291 mmol)in 2 ml CHCl₃ was heated to 65° C. for 18 hours. The cooled reactionmixture was evaporated, followed by addition of 1 mL MeOH. The resultingprecipitate was collected and purified via Supelco Supelclean™ LC-Si SPEtube, 6 mL (1 g) (CH₂Cl₂ to 4% MeOH/CH₂Cl₂) and MS/HPLC (0.0249 g, massspec. M+1=393).

Example 1052-{[1-(Hydroxymethyl)cyclopentyl]amino}-6-(2-methylbenzyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0504]

[0505] A mixture of sulfone (prepared in similar fashion to sulfone 8)(0.05 g, 0.146 mmol), (1-aminocyclopentyl)methanol (0.033 g, 0.291 mmol)in 2 ml CHCl₃ was heated to 65° C. for 18 hours. The cooled reactionmixture was evaporated, followed by addition of 1 mL MeOH. The resultingprecipitate was collected and purified via Supelco Supelclean™ LC-Si SPEtube, 6 mL (1 g) (CH₂Cl₂ to 4% MeOH/CH₂Cl₂) and MS/HPLC (0.0155 g, massspec. M+1=379).

Example 1066-Benzyl-2-{[1-(hydroxymethyl)cyclopentyl]amino}-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0506]

[0507] A mixture of sulfone (prepared in similar fashion to sulfone 8)(0.05 g, 0.152 mmol), (1-aminocyclopentyl)methanol (0.033 g, 0.291 mmol)in 1 ml CHCl₃ was heated to 65° C. for 18 hours. Another 0.020 g of(1-aminocyclopentyl)methanol was added and the mixture heated at 65° C.for 18 hours. The cooled reaction mixture was evaporated, followed byaddition of 1 mL MeOH. The resulting precipitate was collected andpurified via Supelco Supelclean™ LC-Si SPE tube, 6 mL (1 g) (CH₂Cl₂ to1% MeOH/CH₂Cl₂) and MS/HPLC (0.0345 g, mass spec. M+1=365).

Example 107N-[6-(2,4-Difluoro-phenoxy)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3d]pyrimidin-2-y]-N-(tetrahydro-pyran-4-yl)-acetamide

[0508]

[0509] A mixture of6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(Example 23) (1.0 g, 2.57 mmol), N,N-diisopropylethylamine (0.498 g,0.67 mL, 3.86 mmol) in acetic anhydride (1.42 g, 1.02 mL, 13.9 mmol) washeated to 123-127 C for 2 hours. The volatiles were evaporated at 60° C.to provide a thick residue which was dissolved in 4 mL of acetone at67-70° C. To the resulting solution was added 5 mL of hexane maintaininga temperature of 53-55° C. This mixture was allowed to cool to ambienttemperature over 18 hours. The resulting solid was filtered and washedwith 3×3 mL of 1:2 acetone:hexane. The rinsed solid was suspended in 5mL of hexane and heated to reflux for 45 minutes. After cooling toambient temperature, the slurry was filtered and the solid washed withhexane and dried under vacuum. (0.903 g, mass spec. M+1=431,MP=185.3-186.9° C.).

Example 108 Preparation of ethyl4-{[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate

[0510]

[0511] A mixture of sulfone 2 (1.0 g, 2.86 mmol) and ethyl4-amino-1-piperidinecarboxylate (0.98 mL, 5.73 mmol) in 5 mL of1-methyl-2-pyrrolidinone was stirred at 120° C. for 2 hours and thenpoured into water (200 mL) and stirred at room temperature for 1 hour.Filtration followed by drying provided the free amine. A portion of thisproduct (0.050 g, 0.113 mmol) was dissolved in methanol (1-2 mL) andhydrochloric acid in ether (1M, 1 eq) was added. Isolation of the solidvia filtration, followed by rinsing with ether and drying provided 0.038g of the desired product as the hydrochloride salt (MP=171.2-183.5° C.).

Example 109 Preparation of6-(2-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one:

[0512] Step A: Preparation of6-(2-fluorophenoxy)-8-methyl-2-(4-piperidylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0513] A mixture of the free base of ethyl4-{[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate(0.500 g, 1.13 mmol) and iodotrimethylsilane (0.32 mL, 2.27 mmol) in 5mL dichloromethane was refluxed. After 4 hours, additionaliodotrimethylsilane (0.32 mL, 2.27 mmol) was added and the reactionstirred at room temperature for 3 days. The reaction was diluted withmethanol and evaporated, with the residue taken up in a methanolicsolution of sodium methoxide (0.5 M, 9.1 mL) and re-evaporated. Theresulting solids were washed with dichloromethane and dried in vacuo toyield 540 mg of the desired free aminopiperidine.

[0514] Step B: Preparation of6-(2-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0515] A mixture of aminopiperidine (0.125 g, 0.338 mmol), sodiumcarbonate (0.072 g, 0.677 mmol), and benzenesulfonyl chloride (0.052 mL,0.406 mmol) in 4 ml dichloromethane was stirred at room temperature forfour days. The reaction mixture was purified by column chromatography(SiO₂, CH₂Cl₂/MeOH/NH₃OH—95/4/1). The column fractions were combined andconcentrated under reduced pressure to provide the free amine. This freeamine (0.040 g, 0.078 mmol) was dissolved in ethyl acetate (1-2 mL) andhydrochloric acid in ether (1M, 1 eq) was added. Isolation of the solidvia filtration, followed by rinsing with ether and drying provided 0.032g of the desired product as the hydrochloride salt (MP=130.0-135.0° C.).

Example 110 Preparation of6-(2-ethoxy-4-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one:

[0516] Step A: Preparation of6-(2-ethoxy-4-fluorophenoxy)-8-methyl-2-(4-piperidylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0517] A mixture of ethyl4-{[6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate(Example 70, 1.0 g, 2.16 mmol) and potassium hydroxide (2.43 g, 43.2mmol) in 20 mL of ethanol was refluxed for 17 hours, after which 0.5 mLwater was added and reflux continued for another 20 hours beforeevaporating the reaction volume under reduced pressure. The residue wastaken up in 100 ml water and chilled in an ice bath before acidifyingwith dropwise concentrated HCl. The acidic aqueous solution wasextracted with dichloromethane (2×) before being re-alkalized withsodium hydroxide and re-extracted with dichloromethane (2×). The organicextracts from the alkaline aqueous solution were combined, dried withmagnesium sulfate, and dried in vacuo to yield the aminopiperidine(M+1=414.1).

[0518] Step B: Preparation of6-(2-ethoxy-4-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0519] A portion of the above piperidine (0.150 g, 0.387 mmol) was takenup in 2 mL dichloromethane with sodium carbonate (0.082 g, 0.774 mmol)and α-toluenesulfonyl chloride (0.085 mL, 0.465 mmol) and stirred atroom temperature for 17 hours. The reaction mixture was purified bycolumn chromatography (SiO₂, CH₂Cl₂/MeOH—95/5). The column fractionswere combined and concentrated under reduced pressure to provide thefree amine. This free amine (0.076 g, 0.140 mmol) was dissolved inmethanol (1-2 mL) and hydrochloric acid in ether (1M, 1 eq) was addedbefore evaporation under reduced pressure Isolation of the solid byrinsing with ether, filtration, and drying in vacuo provided 0.031 g ofthe desired product as the hydrochloride salt (MP=134.6-187.3° C.).

Example 111 Preparation of6-(2-methyl-4-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0520] Step A: Preparation of6-(2-methyl-4-fluorophenoxy)-8-methyl-2-methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0521] To a mixture of4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (preparationdescribed in Example 1) (7.3 g, 39.6 mmol) and methyl2-methyl-4-fluorophenoxyacetate (prepared as in Example 4 substituting2-methyl-4-fluorophenol for 2-fluorophenol), (11.8 g, 59.4 mmol) in 80mL of 1-methyl-2-pyrrolidinone was added potassium carbonate (11.0 g,79.3 mmol). The reaction mixture was heated to 120° C. and after 3 days,additional phenoxyacetate (15.0 g, 75.7 mmol) was added. After 18 hoursof stirring at 120° C., the reaction was cooled to room temperature andwater (1 L) was added. The suspension was stirred for 2 hours thenextracted with ethyl acetate (2×). The combined extracts were washedwith water (3×) and saturated brine, dried with magnesium sulfate, andevaporated in vacuo. The crude solid (10.1 g) was washed with ethylether and ethyl acetate, then dried in vacuo, yielding 2.3 g of the puresulfide (mass spec. M+1=332).

[0522] Step B: Preparation of6-(2-methyl-4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0523] The sulfide (2.3 g, 6.9 mmol) was dissolved in 100 mL ofmethylene chloride and 3-chloroperbenzoic acid (77%, 3.6 g, 20.6 mmol)was added. The mixture was stirred at room temperature for 2 hours, thenpoured into aqueous sodium sulfite solution (10%, 100 mL) and stirredfor 2 hours at room temperature before partitioning. The organic layerwas washed with half-saturated aqueous sodium bicarbonate solution (3×,100 mL), dried with magnesium sulfate, and evaporated. The resultantsolid was stirred with ether for 1 hour and filtered to yield thesulfone.

[0524] Step C: Preparation of6-(2-methyl-4-fluorophenoxy)-8-methyl-2-(4-piperidylamino)pyrido[2,3-d]pyrimidin-7(8H)-one:

[0525] The piperidine ethyl carboxylate (prepared from the sulfonedescribed in Step B and ethyl 4-amino-1-piperidine carboxylate insimilar fashion as described in example 70). was isolated as thehydrochloride salt (mp 184.0-210.3° C.). 1.03 g of this ethyl carbamate(2.26 mmol) and potassium hydroxide (4.81 g, 85.7 mmol) in 60 ml ethanolwas refluxed for 3 days and evaporated in vacuo. The residue wasdissolved in aqueous hydrochloric acid (2M) and extracted withdichloromethane (2×), then chilled in an ice bath and re-alkalized withsolid sodium hydroxide. The resultant oily precipitate was decanted andwashed with methanol and dichloromethane, dried with sodium carbonate,and evaporated in vacuo to yield 0.550 g of the desired piperidine.

[0526] Step D: Preparation of6-(2-methyl-4-fluorophenoxy)-8-methyl-2-{[(1-benzylsulfonyl)piperidiny-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one

[0527] A mixture of the piperidine (0.125 g, 0.326 mmol), sodiumcarbonate (0.069 g, 0.652 mmol), and benzenesulfonyl chloride (0.050 ml,0.391 mmol) in 2 ml dichloromethane was stirred at room temperature for5 days and purified by column chromatography (SiO₂, CH₂Cl₂/MeOH—95/5).The column fractions were combined and concentrated under reducedpressure to provide the free amine. This free amine (0.185 g, 0.353mmol) was dissolved in ethyl acetate (1-2 mL) and hydrochloric acid inether (1M, 1 eq) was added. Isolation of the solid by filtration,rinsing with ether, and drying in vacuo provided 0.156 g of thehydrochloride salt (MP=115.2-122.9° C.).

Example 112 Preparation of6-(2,4-difluorophenoxy)-8-methyl-2-(N¹-methylsulfonyl)-1,3-diaminopentane)pyrido[2,3-d]pyrimdin-7(8H)-one

[0528] Step A: Preparation of 6-(2,4-difluorophenoxy)-8-methyl-2-(N¹-(carbobenzyloxy)-1,3-diaminopentane)pyrido[2,3-d]pyrimidin-7(8H)-one

[0529] Sulfone 5 (0.47 g, 6.4 mmol) was dissolved in anhydrous THF towhich was added N¹-(carbobenzyloxy)-1,3-diaminopentane (Org. Prep. andProceed. Int., 30(3), 339-348 (1998)), (1.52 g, 6.4 mmol) and stirredovernight at 230 under nitrogen. Concentrated under vacuum to give crudeoil that was dissolved up with dichloromethane washed with saturatedsodium bicarbonate, washed with brine and dried (MgSO₄). Filtered andconcentrated to give crude oil which was chromatographed on silica geleluding with 2% methanol in dichloromethane to give 0.657 g6-(2,4-difluorophenoxy)-8-methyl-2-(N¹-(carbobenzyloxy)-1,3-diaminopentane)pyrido[2,3-d]pyrimidin-7(8H)-one (mass spec. M+1=524)

[0530] Step B: Preparation of 6-(2,4-difluorophenoxy)-8-methyl-2-(N¹-methylsulfonyl)-1,3-diaminopentane) pyrido[2,3-d]pyrimidin-7(8H)-one

[0531] To a THF solution of6-(2,4-difluorophenoxy)-8-methyl-2-(N¹-(carbobenzyloxy)-1,3-diaminopentane)pyrido[2,3-d]pyrimidin-7(8H)-one(0.65 g, 1.2 mmol) was added 10% Pd-C (0.13 g) and stirred for 4 hrs at23° C. under hydrogen gas. Filtered and concentrated under vacuum.Residue dissolved up with 10 ml dichloromethane and cooled to ⁻10° C.;added pyridine (5 ml, 62 mmol) and methanesulfony chloride (0.070 ml,0.86 mmol) and stirred. Concentrated under vacuum and chromatographed onsilica gel eluding with 1% methanol in dicloromethane to give 0.121 g6-(2,4-difluorophenoxy)-8-methyl-2-(N¹-methylsulfonyl)-1,3-diaminopentane)pyrido[2,3-d]pyrimidin-7(8H)-onewhich was dissolved in anhydrous ether and converted to hydrochloridesalt (mass spec. M+1=468, m.p. 178.6-181.2° C.)

Example 113 Preparation of 4-Amino-2-methylthiopyrimidine-5-carbaldehyde

[0532]

[0533] Preparation of 3,3-Diethoxy-2-formylpropionitrile Potassium Salt(II)

[0534] To a stirred solution of 3,3-diethoxypropane-nitrile (1,283.80 g,1.98 moles) and methyl formate (148.80 g, 2.48 moles) in anhydrous THF(1.1 L) at 10° C. was added 1.0 M potassium tert-butoxide in THF (2.2 L,2.2 moles). Temperature was maintained in the range of 10° C. to 15° C.throughout the 45 minute addition. Following the addition, the resultingslurry was stirred 2 hours at ambient room temperature. Hexane (400 mL)was then added and stirring was continued for another 20 min. The slurrywas filtered and the cake washed with 1/1 hexanes/THF and driedovernight at 60° C. in a vacuum oven. The yield of pale tan powder was302.5 grams (73.0%). ¹H-NMR (CD₃OD) was consistent with the desiredstructure II.

[0535] Preparation of 4-Amino-2-sulfanylpyrimidine-5-carbaldehyde (III)

[0536] A slurry of thiourea (92.8 g, 1.22 moles) in ethanol (90 mL) washeated under reflux and vigorously stirred. To this slurry was added asuspension of 3,3-diethoxy-2-formylpropionitrile potassium salt II(222.20 g, 1.06 moles) in 25% sodium methoxide/methanol (85.5 mL, 0.37mole) and ethanol (285 mL) in five aliquots over a 10 minute periodwhile maintaining reflux conditions (alternatively, the latter slurrymay be heated to 50° C. to give a homogenous solution for the addition).An additional portion of ethanol (150 mL) was added to facilitatestirring. The thick slurry became a bright yellow color following theaddition and was held under reflux for an additional 1 hour. The mixturewas then cooled and evaporated to near dryness on a rotoevaporator. Theresidue was dissolved in water (940 mL). Crude product was precipitatedfrom solution by the addition of 30% acetic acid (280 mL) and isolatedvia filtration using a medium frit sintered glass filtration funnel. Thecake was washed with water (800 mL). Purification via trituration in hotwater (1 L) for 30 minutes, followed by cooling and filtration gave118.9 grams (72.3%) of product as a bright yellow solid after dryingovernight at 60° C. in a vacuum oven (subsequent preparations havedemonstrated that this trituration is unnecessary). An HPLC gave purityas 98.67%. ¹H-NMR (DMSO-d₆) was consistent with desired structure III.

[0537] Preparation of 4-Amino-2-methylthiopyrimidine-5-carbaldehyde (IV)

[0538] To a solution of 4-amino-2-sulfanyl-pyrimidine-5-carbaldehyde III(100.00 g, 644.4 mmoles) and 325 mesh potassium carbonate (178.10 g,1.29 moles) in acetone (1.5 L) was added iodomethane (128.10 g, 902.2mmoles) dropwise over 20 minutes with mild cooling. The mixture wasstirred at ambient room temperature over the weekend. TLC showedremaining III and an additional aliquot of iodomethane was added (8 mL)and stirring was continued overnight. TLC again showed some IIIremaining and an addition portion of iodomethane was added (8 mL) andstirring was continued another 24 hour period. An HPLC showed 95.9%S-alkylated product and 3.7% of compound III. The reaction mixture wasstripped to near dryness on a rotoevaporator. Water (1 L) was added tothe residue and the product was collected via filtration and washed withwater (200 mL). The product was dried overnight in a vacuum oven at 60°C. Yield was 103.37 grams (94.8%). An HPLC showed 95.8% IV and 4.2% III.

Example 114

[0539] This example illustrates a p38 (MAP) kinase in vitro assay usefulfor evaluating the compounds of the present invention.

[0540] The p-38 MAP kinase inhibitory activity of compounds of thisinvention in vitro was determined by measuring the transfer of theγ-phosphate from γ-³³P-ATP by p-38 kinase to Myelin Basic Protein (MBP), using a minor modification of the method described in Ahn, et al.,J. Biol. Chem. 266:4220-4227 (1991).

[0541] The phosphorylated form of the recombinant p38 MAP kinase wasco-expressed with SEK-1I and MEKK in E. Coli (see, Khokhlatchev, et al.,J. Biol. Chem. 272:11057-11062 (1997)) and then purified by affinitychromatography using a Nickel column.

[0542] The phosphorylated p38 MAP kinase was diluted in kinase buffer(20 mM 3-(N-morpholino)propanesulfonic acid, pH 7.2, 25 ml β-glycerolphosphate, 5 mM ethylene glycol-bis(beta-aminoethylether)-N,N,N′,N′tetraacetic acid, 1 mM sodium ortho-vanadate, 1 mMdithiothreitol, 40 mM magnesium chloride). Test compound dissolved inDMSO or only DMSO (control) was added and the samples were incubated for10 min at 30° C. The kinase reaction was initiated by the addition of asubstrate cocktail containing MBP and γ-³³P-ATP. After incubating for anadditional 20 min at 30° C., the reaction was terminated by adding 0.75%phosphoric acid. The phosphorylated MBP was then separated from theresidual γ-³³P-ATP using a phosphocellulose membrane (Millipore,Bedfrod, Mass.) and quantitated using a scintillation counter (Packard,Meriden, Conn.).

Example 115

[0543] This example illustrates an in vitro assay to evaluate theinhibition of LPS-induced TNF-α: production in THP1 cells.

[0544] The ability of the compounds of this invention to inhibit theTNF-α release was determined using a minor modification of the methodsdescribed in Blifeld, et al. Transplantation, 51:498-503 (1991).

[0545] (a) Induction of TNF biosynthesis:

[0546] THP-1 cells were suspended in culture medium [RPMI (Gibco-BRL,Gailthersburg, Md.) containing 15% fetal bovine serum, 0.02 mM2-mercaptoethanol], at a concentration of 2.5×10⁶ cells/mL and thenplated in 96 well plate (0.2 mL aliquots in each well). Test compoundswere dissolved in DMSO and then diluted with the culture medium suchthat the final DMSO concentration was 5%. Twenty five 1L aliquots oftest solution or only medium with DMSO (control) were added to eachwell. The cells were incubated for 30 min., at 37° C. LPS (Sigma, St.Louis, Mo.) was added to the wells at a final concentration of 0.5μg/ml, and cells were incubated for an additional 2 h. At the end of theincubation period, culture supernatants were collected and the amount ofTNF-α: present was determined using an ELISA assay as described below.

[0547] (b) ELISA Assay:

[0548] The amount of human TNF-α: present was determined by a specifictrapping ELISA assay using two anti-TNF-α antibodies (2TNF-H12 and2TNF-H34) described in Reimund, J. M., et al. GUT. Vol. 39(5), 684-689(1996).

[0549] Polystyrene 96-well plates were coated with 50 μl per well ofantibody 2TNF-H12 in PBS (10 μg/mL) and incubated in a humidifiedchamber at 4° C. overnight. The plates were washed with PBS and thenblocked with 5% nonfat-dry milk in PBS for 1 hour at room temperatureand washed with 0.1% BSA (bovine serum albumin) in PBS.

[0550] TNF standards were prepared from a stock solution of humanrecombinant TNF-α: (R&D Systems, Minneapolis, Minn.). The concentrationof the standards in the assay began at 10 ng/mL followed by 6 half logserial dilutions.

[0551] Twenty five μL aliquots of the above culture supernatants or TNFstandards or only medium (control) were mixed with 25 μL aliquots ofbiotinylated monoclonal antibody 2TNF-H34 (2 μg/mL in PBS containing0.1% BSA) and then added to each well. The samples were incubated for 2hr at room temperature with gentle shaking and then washed 3 times with0.1% BSA in PBS. 50 μl of peroxidase-streptavidin (Zymed, S. SanFrancisco, Calif.) solution containing 0.416 μg/mL ofperoxidase-streptavidin and 0.1% BSA in PBS was added to each well. Thesamples were incubated for an additional 1 hr at room temperature andthen washed 4 times with 0.1% BSA in PBS. Fifty μL of O-phenylenediaminesolution (1 μg/mL O-phenylene-diamine and 0.03% hydrogen peroxide in0.2M citrate buffer pH 4.5) was added to each well and the samples wereincubated in the dark for 30 min., at room temperature. Optical densityof the sample and the reference were read at 450 nm and 650 nm,respectively. TNF-α levels were determined from a graph relating theoptical density at 450 nm to the concentration used.

[0552] The IC₅₀ value was defined as the concentration of the testcompound corresponding to half-maximal reduction in 450 nm absorbance.

Example 116

[0553] This example illustrates an in vivo assay to evaluate theinhibition of LPS-induced TNF-α production in mice (or rats).

[0554] The ability of the compounds of this invention to inhibit theTNF-α: release, in vivo, was determined using a minor modification ofthe methods described in described in Zanetti, et. al., J. Immunol.,148:1890 (1992) and Sekut, et. al., J. Lab. Clin. Med., 124:813 (1994).

[0555] Female BALB/c mice weighing 18-21 grams (Charles River,Hollister, Calif.) were acclimated for one week. Groups containing 8mice each were dosed orally either with the test compounds suspended ordissolved in an aqueous vehicle containing 0.9% sodium chloride, 0.5%sodium carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol(CMC vehicle) or only vehicle (control group). After 30 min., the micewere injected intraperitoneally with 20 μg of LPS (Sigma, St. Louis,Mo.). After 1.5 h, the mice were sacrificed by CO₂ inhalation and bloodwas harvested by cardiocentesis. Blood was clarified by centrifugationat 15,600× g for 5 min., and sera were transferred to clean tubes andfrozen at −20° C. until analyzed for TNF-α by ELISA assay (BiosourceInternational, Camarillo, Calif.) following the manufacturer's protocol.

[0556] Representative compounds of the present invention are shown inTable 1 below. Compounds of Table 1 have IC₅₀ activity against p38kinase in the range of from about 0.1 to 5000 nM, with the majoritybeing between 1 to 1000 nM and are surprisingly selective for p38 kinaserelative to cyclin-dependent kinases and tyrosine kinase. TABLE 1Representative compounds of Formula I. Mass MOL STRUCTURE M. Pt. SpecExample I-1

182.1-183.8 I-2

I-3

I-4

I-5

I-6

200.9 to 201.6 I-7

197-197.4 I-8

197.0 to 197.4 I-9

I-10

210.4-231.5 I-11

235-253 I-12

230.7-232.8 57 I-13

224.2-225 I-14

253.2-253.9 M + 1 = 385 26 I-15

253.8-254.7 I-16

M + 1 = 387 I-17

387 I-18

M + 1 = 353 21 I-19

M + 1 = 465 33 I-20

M + = 371 22 I-21

183-191 M + = 370 I-22

208-211 M + = 389 23 I-23

M + 1 = 430 I-24

M + 1 = 465 32 I-25

M + 1 = 448 29 I-26

M + 1 = 448 I-27

M + 1 = 371 I-28

M + 1 = 448 I-29

M + 1 = 466 I-30

M + 1 = 337 I-31

M + 1 = 371 I-32

M + 1 = 371 I-33

M + 1 = 355 I-34

M + 1 = 355 35 I-35

M + 1 = 373 I-36

M + 1 = 355 36 I-37

M + 1 = 389 52 I-38

M + 1 = 403 I-39

M + 1 = 375 I-40

M + 1 = 380 80 I-41

M + 1 = 373 40 I-42

245.2-246.1 M + 1 = 478 79 I-43

203.2-204 M + 1 = 377 63 I-44

245.2-246.1 I-45

214.7-226.8 I-46

M + 1 = 343 37 I-47

M + 1 = 456 I-48

M + 1 = 331 38 I-49

M + 1 = 356 I-50

M + 1 = 343 39 I-51

255.5-261.4 M + 1 = 494 78 I-52

249-.4-251.2 I-53

215.2-218.1 I-54

M + 1 = 361 41 I-55

M + 1 = 345 I-56

M + 1 = 371 I-57

122.1-161.2 I-58

M + 1 = 378 66 I-59

M + 1 = 400 I-60

M + 1 = 398 42 I-61

M + 1 = 383 43 I-62

210.4-211.2 I-63

207.2-207.5 I-64

M + 1 = 341 44 I-65

M + 1 = 345 45 I-66

M + 1 = 372 46 I-67

M + 1 = 329 I-68

M + 1 = 301 I-69

M + 1 = 471 I-70

M + 1 = 367 67 I-71

188.8-189.7 M + 1 = 403 55 I-72

109.4-111.3 M + 1 = 405 65 I-73

180.2-183.9 M + 1 = 359 I-74

M + 1 = 442 I-75

5 M + 1 = 419 56 I-76

210-211 M + 1 = 407 69 I-77

222.7-224.8 M + 1 = 407 I-78

242.3-242.6 M + 1 = 381 74 I-79

248.2- M + 1 = 430 75 I-80

239.3-240.5 I-81

266-268 M + 1 = 457 I-82

234.9-236.1 I-83

233.9-235.5 M + 1 = 443 72 I-84

239.7-240.4 I-85

188-196 I-86

243.6-244.7 I-87

212.8-213.5 M + 1 = 377 60 I-88

M + 1 = 359 I-89

M + 1 = 414 I-90

M + 1 = 412 47 I-91

M + 1 = 373 48 I-92

M + 1 = 392 I-93

M + 1 = 392 49 I-94

M + 1 = 357 I-95

201.8-202.5 M + 1 = 421 57 I-96

251.7-254.9 M + 1 = 437 58 I-97

216.3-218.1 M + 1 = 441 I-98

253.4-257.8 M + 1 = 363 I-99

M + 1 = 389 I-100

227.9-228.8 M + 1 = 389 77 I-101

I-102

210.8-211.8 M + 1 = 391 I-103

M + 1 = 474 31 I-104

M + 1 = 358 I-105

M + 1 = 384 I-106

M + 1 = 398 I-107

M + 1 = 315 I-108

M + 1 = 378 81 I-109

180.2-182.2 M + 1 = 409 71 I-110

176.7-177.7 M + 1 = 391 59 I-111

208.7-212.4 I-112

242.7-243.1 I-113

211.8-213 M + 1 = 373 68 I-114

193.7-194.3 I-115

207.3-207.6 M + 1 = 421 I-116

M + 1 = 329 I-117

222.1-222.8 M + 1 = 437 I-118

174.6-175.2 M + 1 = 391 I-119

104.3-107.5 M + 1 = 391 53 I-120

223.4-225 M + 1 = 528 30 I-121

107.2-111.4 M + 1 = 373 I-122

250.5-253.7 I-123

178.2-179.6 M + 1 = 327 34 I-124

130.6-132.2 M + l = 405 62 I-125

198.6-200.3 M + 1 = 385 61 I-126

M + 1 = 357 I-127

M + 1 = 387 50 I-128

M + 1 = 466 I-129

M + 1 = 369 51 I-130

203.6-207.5 I-131

224-224.9 I-132

232.4-233.7 I-133

197-204 M + 1 = 462 70 I-134

197.0-204.0 I-135

mp = 135-145 M + 1 = 399 28 I-136

M + 1 = 397 I-137

M + 1 = 398 I-138

205.0-207.0 I-139

M + 1 = 427 I-140

M + 1 = 423 I-141

149-180 M + 1 = 453 I-142

240.8-242.6 M + 1 = 287 20 I-143

I-144

I-145

I-146

I-147

60.3-61.4 (M + H) += 3 87 55 I-148

246-247.5 M + 1 = 401 25 I-149

233-235.7 I-150

209-211.2 I-151

198.4-201.6 M + 1 = 369 24 I-152

243.1-246.3 M + 1 = 361 73 I-153

254.5-256.1 I-154

154-175 M + 1 = 375 64 I-155

246-250 M + 1 = 379 76 I-156

229.5-230.2 M + l = 383 27 I-157

243.2-243.8 I-158

179.6-182.7 I-159

254.4-255.7 I-160

162.9-170.5 M + 1 = 371 54 I-161

178.3-179.3 I-162

233.8-234.6 I-163

215.2-218.1 I-164

85.0-89.0 I-165

201.5-203.0 I-166

[0557] TABLE 2 Additional representative compounds of Formula IStructure MS MP Example 2-1 

171.2-183.5 108 2-2 

M + 1 = 369 99 2-3 

134.6-187.3 110 2-4 

155.0-185.8 2-5 

M + 1 = 378 100 2-6 

M + 1 = 395 101 2-7 

M + 1 = 395 102 2-8 

M + 1 = 382 103 2-9 

115.2-122.9 111 2-10

136.0-140.0 2-11

194.0-197.0 2-12

150.5-153.0 2-13

130.0-135.0 109 2-14

130.0-135.0 2-15

M + 1 = 393 104 2-16

M + 1 = 379 105 2-17

M + 1 = 365 106 2-18

(M + H) + 416 195-201 84 2-19

419.1MH+ 200-202 87 2-20

393MH+   196-197.2 86 2-21

(M + H) + 374 2-22

(M + H) + 452 199-204 2-23

(M + H) + 388 257.1-257.8 2-24

(M + H) = 390 89 2-25

467 178.6-181.2 112 2-26

(M + H) + 376   216-217.9 93 2-27

(M + H) + 389 200.9-206.7 2-28

(M + H) + 346   222-230.6 2-29

414.43MH 239-244 2-30

(M + H) + 403 199.1-205.9 95 2-31

388MH 237.5-239   88 2-32

402MH   151-164.8 2-33

(M + H) = 418 136.4-131.0 92 2-34

(M + H) = 402 198.1-199.7 2-35

(M + H) = 374 212.2-214.0 2-36

(M + H) = 460 91 2-37

(M + H) = 432 90 2-38

(M + H) + 402   197-198.5 94 2-39

(M + H) + 405 154.5-156.0 97 2-40

M + H = 405 226.4-227.7 98 2-41

(M + H) + 386 210.3-219.8 2-42

M + 1 = 417 175.3°-176.9° 2-43

2-44

239.5 to 249.7 2-45

(M + H) = 419 174.9-176.3 96 2-46

148-152 2-47

185.3-186.9 107 2-48

(M + H) = 452 199-204 85 2-49

2-50

2-51

2-52

[0558] The foregoing discussion of the invention has been presented forpurposes of illustration and description. The foregoing is not intendedto limit the invention to the form or forms disclosed herein. Althoughthe description of the invention has included description of one or moreembodiments and certain variations and modifications, other variationsand modifications are within the scope of the invention, e.g., as may bewithin the skill and knowledge of those in the art, after understandingthe present disclosure. It is intended to obtain rights which includealternative embodiments to the extent permitted, including alternate,interchangeable and/or equivalent structures, functions, ranges or stepsto those claimed, whether or not such alternate, interchangeable and/orequivalent structures, functions, ranges or steps are disclosed herein,and without intending to publicly dedicate any patentable subjectmatter. All publications, patents, and patent applications cited hereinare hereby incorporated by reference in their entirety for all purposes.

What is claimed is:
 1. A compound of the Formula I or II

or pharmaceutically acceptable salts thereof, wherein: Z is N or CH; Wis NR²; X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S, or CR⁵R⁶ (whereR⁵ and R⁶ are independently hydrogen or alkyl) or C═O; X is O or NR; Ar¹is aryl or heteroaryl; R² is hydrogen alkyl, acyl, alkoxycarbonyl,aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl or —R²¹—R²²where R²¹ is alkylene or —C(═O)— and R²² is alkyl or alkoxy; R¹ ishydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl,heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl,heterocyclylalkyl, R¹²—SO₂-heterocycloamino (where R¹² is haloalkyl,aryl, aryalkyl, heteroaryl or heteroaralkyl), —Y¹—C(O)—Y²—R¹¹ (where Y¹and Y² are independently either absent or an alkylene group and R¹¹ ishydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino ordialkylamino), (heterocyclyl)(cycloalkyl)alkyl or(heterocyclyl)(heteroaryl)alkyl; R³ is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl,alkylene-C(O)—R³¹ (where R³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino,monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino orNR³²—Y³—R³³ (where Y³ is —C(O), —C(O)O—, —C(O)NR³⁴, S(O)₂ or S(O)₂NR³;R³², R³⁴ and R³⁵ are independently hydrogen or alkyl; and R³³ ishydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionallysubstituted phenyl) or acyl; R⁷ is hydrogen or alkyl; and R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, —C(O)—R⁸¹(where R⁸¹is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, alkoxy, aryloxy, amino, mono- or di-alkylamino, arylaminoor aryl(alkyl)amino) or R ⁸ and R⁹ together form ═CR⁸²R⁸³ (where R⁸² andR⁸³ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl oroptionally substituted phenyl). or pharmaceutically acceptable saltsthereof,
 2. The compound of claim 1, wherein: Z is N or CH; W is NR² orO; X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S, or CR⁵R⁶ (where R⁵and R⁶ are independently hydrogen or alkyl) or C═O; X² is O or NR⁷; Ar¹is aryl or heteroaryl; R² is hydrogen or alkyl; R¹ is hydrogen, alkyl,haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl,—Y¹—C(O)—Y²—R¹¹ (where Y¹ and Y² are independently either absent or analkylene group and R¹¹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy,amino, monoalkylamino or dialkylamino), (heterocyclyl)(cycloalkyl)alkylor (heterocyclyl)(heteroaryl)alkyl; R³ is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl,alkylene-C(O)—R³¹ (where R³¹ is hydrogen, alkyl, hydroxy, alkoxy, amino,monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino orNR³²—Y³—R³³ (where Y³ is —C(O), —C(O)O—, —C(O)NR³⁴, S(O)₂ or S(O)₂NR⁵;R², R³⁴ and R³⁵ are independently hydrogen or alkyl; and R³³ ishydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionallysubstituted phenyl)or acyl; R⁷ is hydrogen or alkyl; and R⁸ and R⁹ areindependently hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, —C(O)—R⁸¹(where R⁸¹is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, alkoxy, aryloxy, amino, mono- and di-alkylamino, arylaminoor aryl(alkyl)amino) or R⁸ and R⁹ together form ═CR⁸²R⁸³ (where R⁸² andR⁸³ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl oroptionally substituted phenyl).
 3. The compound of claim 2, wherein Z isN.
 4. The compound of claim 3, wherein W is NH.
 5. The compound of claim4, wherein Ar¹ is optionally substituted phenyl.
 6. The compound ofclaim 5, wherein X¹ is O or CH₂.
 7. The compound of claim 6, wherein X¹is O.
 8. The compound of claim 7 wherein R¹ is aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl,heterosubstituted cycloalkyl, heteroalkyl, heterocyclyl orheterocyclylalkyl.
 9. The compound of claim 8, wherein R¹ isheteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl or heterocyclyl.
 10. The compound of claim 9, wherein R¹ isheterocyclyl.
 11. The compound of claim 9, wherein R¹ is heteroalkyl.12. The compound of claim 11, wherein R¹ is hydroxyalkyl.
 13. Thecompound of claim 9, wherein Ar¹ is 2-substituted-phenyl,4-substituted-phenyl or 2,4-disubstituted-phenyl.
 14. The compound ofclaim 13, wherein Ar¹ is 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methyl or 2,4-difluorophenyl. 15.The compound of claim 8 of Formula I, wherein X² is O and R³ is methyl.16. The compound of claim 15, wherein R¹ is heteroalkylsubstitutedcycloalkyl, heterosubstituted cycloalkyl, heteroalkyl or heterocyclyl.17. The compound of claim 16, wherein R¹ is heterocyclyl.
 18. Thecompound of claim 16, wherein R¹ is heteroalkyl.
 19. The compound ofclaim 18, wherein R¹ is hydroxyalkyl.
 20. The compound of claim 16wherein Ar¹ is 2-substituted-phenyl, 4-substituted-phenyl or2,4-disubstituted-phenyl.
 21. The compound of claim 20, wherein Ar¹ is2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-fluoro-4-methylphenylor 2,4-difluorophenyl.
 22. The compound of claim 8 of Formula I, whereinX² is NR⁷ and R³ is methyl.
 23. The compound of claim 22, wherein R¹ isheteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl or heterocyclyl.
 24. The compound of claim 23, wherein R¹ isheterocyclyl.
 25. The compound of claim 23, wherein R¹ is heteroalkyl.26. The compound of claim 25, wherein R¹ is hydroxyalkyl.
 27. Thecompound of claim 23, wherein Ar¹ is 2-substituted-phenyl,4-substituted-phenyl or 2,4-disubstituted-phenyl.
 28. The compound ofclaim 27, wherein Ar¹ is 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl,2-fluoro-4-methylphenyl or 2,4-difluorophenyl.
 29. The compound of claim8 of Formula II, wherein R⁸ is hydrogen and R⁹ is alkyl, alkylsulfonylor —C(O)—R⁸¹ (where R⁸¹ is alkyl, alkoxy, aryloxy, amino, monoalkylaminoor dialkylamino).
 30. The compound of claim 29, wherein R¹ isheteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl,heteroalkyl or heterocyclyl.
 31. The compound of claim 30, wherein R¹ isheterocyclyl.
 32. The compound of claim 31, wherein R¹ is heteroalkyl.33. The compound of claim 32, wherein R¹ is hydroxyalkyl.
 34. Thecompound of claim 30, wherein Ar¹ is 2-substituted-phenyl,4-substituted-phenyl or 2,4-disubstituted-phenyl.
 35. The compound ofclaim 35, wherein Ar¹ is 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl,2-fluoro-4-methylphenyl or 2,4-difluorophenyl.
 36. The compound of claim21, wherein Ar¹ is 2,4-difluoro-phenyl and R¹ istetrahydro-2H-pyran-4-yl, i.e.,6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one.37. The compound of claim 21, wherein Ar¹ is 2,4-difluoro-phenyl and R¹is tetrahydro-2H-pyran-4-yl, i.e.,6-(2,4-difluorophenoxy)-8-propyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one.38. The compound of claim 21, wherein Ar¹ is 2,4-difluoro-phenyl and R¹is tetrahydro-2H-pyran-4-yl, i.e.,6-(2,4-difluorophenoxy)-8-cyclopropyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one.39. The compound of claim 19, wherein Ar¹ is 2,4-difluorophenyl and R¹is1,3-dimethyl-3-hydroxy-butyl, i.e.,6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1,3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one.40. The compound of claim 39 that is6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1(S),3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one.
 41. Thecompound of claim 39 that is 6-(2,4-Difluoro-phenoxy)-2-(3-hydroxy-1(R),3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one.
 42. Thecompound of claim 1 of Formula I, wherein: R² is acyl, alkoxycarbonyl,aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl or —R²—R²²where R²¹ is alkylene or —C(═O)— and R²² is alkyl or alkoxy.
 43. Thecompound of claim 42, wherein R¹ is heteroalkyl or heterocyclyl.
 44. Thecompound of claim 43, wherein, R¹ is heterocyclyl.
 45. The compound ofclaim 44, wherein X¹ is O, X² is O and R³ is methyl.
 46. The compound ofclaim 45, wherein R² is acyl.
 47. The compound of claim 46, wherein Ar¹is 2,4-difluoro-phenyl, R¹ is tetrahydro-2H-pyran-4-yl and R² is acetyl48. A composition comprising: (a) a pharmaceutically acceptableexcipient; and (b) a compound of claim 1 or pharmaceutically acceptablesalts thereof.
 49. A method for preparing a sulfide compound of theformula:

wherein: Z is N or CH; X¹ is O, NR⁴ (where R⁴ is hydrogen or alkyl), S,CR⁵R⁶ (where R⁵ and R⁶ are independently hydrogen or alkyl) or C═O; X²is O; Ar¹ is aryl or heteroaryl; R is alkyl or aryl; R³ is hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl,heteroalkyl, cyanoalkyl, acyl, alkylene-C(O)—R³¹ (where R³¹ is hydrogen,alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino,monoalkylamino, dialkylamino or NR³²—Y³¹—R³³ (where Y³ is —C(O),—C(O)O—, —C(O)NR³⁴, S(O)₂ or S(O)₂NR³⁵; R³², R³⁴ and R³⁵ areindependently hydrogen or alkyl; and R³³ is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl or optionally substituted phenyl); saidmethod comprising the steps of: contacting an aldehyde of the formula:

 with an aryl compound of the formula:

 wherein X³ is —C(═O)—OR′ and R′ is alkyl,  under conditions sufficientto produce said sulfide compound.
 50. The method of claim 49, wherein Zis N
 51. The method of claim 50, wherein R³ is hydrogen.
 52. The methodof claim 49 further comprising producing a sulfonyl compound of theformula:

wherein R, Z, R³, X¹, X² and Ar¹ are as defined in claim 36, comprisingexposing said sulfide compound to oxidizing conditions to produce saidsulfonyl compound.
 53. The method of claim 52, wherein said oxidizingconditions comprise MCPBA, Oxone®, periodate or a rhenium peroxidespecies.
 54. A method of preparing a compound of Formula I of claim 1comprising the steps of: contacting a compound of Formula IV

where L is a leaving group; with an amine R¹R²NH under nucleophilicdisplacement conditions.
 55. The method of claim 54, wherein L is agroup RS(O)_(n)— where R is an alkyl or phenyl group and n is an integerfrom 0 to
 2. 56. A compound of Formula I′ or II″

wherein: Z is N or CH; W is S, S(O), S(O)₂ or O; X¹ is O, NR⁴ (where R⁴is hydrogen or alkyl), S, or CR⁵R⁶ (where R⁵ and R⁶ are independentlyhydrogen or alkyl) or C═O; X² is O or NR^(7;) Ar¹ is aryl or heteroaryl;R¹⁰ is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl, or R¹⁰Wtogether form a leaving group or hydroxy; R³ is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl,cyanoalkyl, alkylene-C(O)—R³¹ (where R³¹ is hydrogen, alkyl, hydroxy,alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino,dialkylamino or NR³²—Y³—R³³ (where Y³ is —C(O), —C(O)O—, —C(O)NR³⁴,S(O)₂, or S(O)₂NR³⁵; R³², R³⁴ and R³⁵ are independently hydrogen oralkyl; and R³³ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl or optionally substituted phenyl) or acyl; R⁷ is hydrogen oralkyl; and R⁸ and R⁹ are independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl,—C(O)—R⁸¹ (where R⁸¹is alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- anddi-alkylamino, arylamino or aryl(alkyl)amino) or R⁸ and R⁹ together form═CR⁸²R⁸³ (where R⁸² and R⁸³ are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkyl or optionally substituted phenyl).
 57. Amethod for treating p38 mediated disorder comprising administering to apatient in need of such treatment, an effective amount of a compound ofclaim
 1. 58. The method of claim 57, wherein said p38 mediated disorderis arthritis, Crohns disease, irritable bowel syndrome adult respiratorydistress syndrome or chronic obstructive pulmonary disease.
 59. Themethod of claim 57, wherein said p38 mediated disorder is Alzheimer'sdisease.